Sorafenib is a widely-adopted kinase inhibitor in anticancer therapy for advanced hepatocellular carcinoma (HCC) and the individualized pharmacological resistance to sorafenib is still an unresolved issue. Whether histone H3K9 methyltransferase SETDB1, which represses chromatin states and promotes various oncogenesis, modulate this process is still elusive. The analysis from both TCGA-LIHC cohort and our clinical HCC patient samples revealed that hepatic SETDB1 expression positively correlates with the prognosis of HCC patients receiving sorafenib therapy. Meanwhile, SETDB1 silencing diminished the cytotoxic effects of sorafenib in hepatoma cells. Mechanistically, SETDB1 knockdown led to mitochondrial dysfunction, including reduced mitochondrial membrane potential, mitochondria superoxide (mSOX), mitochondrial DNA (mtDNA) content, increased fission and DRP1S616 phosphorylation (pDRP1S616) in HepG2 cells. Not only did mSOX fluctuation modulate the sensitivity to sorafenib, but DRP1 activity-silenced counterpart pDRP1S616A inactivation also elevated the susceptibility to sorafenib and the corresponding mSOX and mtDNA content. Finally, pDRP1S616 IHC staining in clinical samples showed that hepatic pDRP1S616 level negatively correlates with the prognosis of HCC patients with sorafenib therapy as well. We first demonstrated that SETDB1 knockdown reduced the susceptibility to sorafenib through enhancing mitochondrial pDRP1S616 in hepatoma cells and hepatic SETDB1 expression might be a potential indicator for clinical HCC sorafenib therapy.

Globally, among numerous cancer subtypes, breast cancer (BC) is one of the most prevalent forms of cancer affecting the female population. A female's family history significantly increases her risk of developing breast cancer. BC is caused by aberrant breast cells that proliferate and develop into tumors. It is estimated that 5-10% of breast carcinomas are inherited and involve genetic mutations that ensure the survival and prognosis of breast cancer cells. The most common genetic variations are responsible for hereditary breast cancer but are not limited to p53, BRCA1, and BRCA2. BRCA1 and BRCA2 are involved in genomic recombination, cell cycle monitoring, programmed cell death, and transcriptional regulation. When BRCA1 and 2 genetic variations are present in breast carcinoma, p53 irregularities become more prevalent. Both BRCA1/2 and p53 genes are involved in cell cycle monitoring. The present article discusses the current status of breast cancer research, spotlighting the tumor suppressor genes (BRCA1/2 and p53) along with structural activity relationship studies, FDA-approved drugs, and several therapy modalities for treating BC. Breast cancer drugs, accessible today in the market, have different side effects including anemia, pneumonitis, nausea, lethargy, and vomiting. Thus, the development of novel p53 and BRCA1/2 inhibitors with minimal possible side effects is crucial. We have covered compounds that have been examined subsequently (2020 onwards) in this overview which may be utilized as lead compounds. Further, we have covered mechanistic pathways to showcase the critical druggable targets and clinical and post-clinical drugs targeting them for their utility in BC.

Cancers are increasingly common and significantly impact patients' quality of life and longevity. The role of macrophages in tumorigenesis is critical, and natural compounds have long been recognized as valuable sources of bioactive agents for treating this condition. However, no systematic review has been performed on the role of phytochemicals impacting tumorigenesis by M1/M2 macrophage polarization. The aim of this study is to systematically review phytochemicals that relieve tumorigenesis by impacting M1/M2 macrophage polarization and investigate related signaling pathways. This systematic review adheres to PRISMA 2020 guidelines and statements. Scientific databases, MEDLINE, Scopus, and Web of Science, have been searched from inception to October 2023. This review includes English original articles on the role of phytochemicals, whole plant extracts, and polyherbal formulas in ameliorating tumorigenesis through M1/M2 polarization while excluding non-English articles, non-original research, and unrelated studies according to title, abstract, and full-text screening. Shreds of evidence were gathered from cellular and animal studies about the beneficial impacts of phytochemicals against tumorigenesis by impacting M1/M2 macrophage polarization. Critical assessment of in vitro and in vivo studies was performed by the CRIS and ARRIVE guidelines. Due to the high level of heterogeneity of the collected data, only a narrative synthesis was performed. Of 741 collected articles, only 35 remained. Polyphenols are the most highlighted group. Phytochemicals affect cytokines related to M1, such as CD80, CD86, CD64, and iNOS, and M2, like CXCR-1, CXCR-2, and TGF-β, in various cancer models. Together, these compounds exerted protective effects against tumorigenesis in preclinical cancer models. Furthermore, high-quality clinical experiments are recommended to cover the limitations of the current study, which are reliance on preclinical evidence, lack of clinical trials, and exclusion of non-English and grey literature.

Wild-type p53 acts as a tumor suppressor, but p53 is frequently mutated and inactivated in tumor cells, promoting cancer progression, invasion, and metastasis. Thus, compounds that reactivate p53 may be leveraged for cancer treatment, and the development of drugs targeting p53 reactivation is actively progressing. Notably, natural products exhibit diverse structures and biological activities and are used as therapeutic agents for various diseases worldwide. This review discusses the natural products that inhibit p53 degradation through p53-Mdm2 interaction, promote p53 reactivation by inducing conformational changes, and exhibit p53-dependent growth inhibition.

Autoantibodies represent promising diagnostic blood-based biomarkers that may be generated prior to the first clinically detectable signs of cancers. In present study, we aimed to identify a novel optimized autoantibody panel with high diagnostic accuracy for clinical and preclinical esophageal squamous cell carcinoma (ESCC) using machine learning (ML) algorithms.

We identified potential autoantibodies against tumor-associated antigens with serological proteome analysis. Serum autoantibody levels were measured by ELISA. Using a training set (n = 531), 102 models based on ML algorithms were constructed, and Partial Least Squares Generalized Linear Models (plsRglm) was selected out using receiver operating characteristics (ROC), Kolmogorov-Smirnov (K-S) test, and Population Stability Index (PSI), and further validated through an internal validation set (n = 413), external validation set 1 (n = 371), and external validation set 2 (n = 202). Then, we validated the ability of plsRglm model in predicting preclinical ESCC by a nested case-control study (24 preclinical ESCCs and 112 matched controls) within a population-based prospective cohort study.

ROC analysis, K-S test, and PSI showed that plsRglm model based on four autoantibodies (ALDOA, ENO1, p53, and NY-ESO-1) exhibited the better diagnostic performance and robustness, which provided a high diagnostic accuracy in diagnosing ESCC with the respective AUCs (sensitivities and specificities) of 0.860 (68.8% and 90.4%) in the training set, 0.826 (65.3% and 89.1%) in the internal validation set, and 0.851 (69.2% and 87.3%) in the external validation set 1. For early-stage ESCC, this signature also maintained diagnostic performance [0.817 (62.3% and 90.4%) in the training set; 0.842 (62.5% and 89.1%) in the internal validation set; 0.854 (63.2% and 87.3%) in the external validation set 1; and 0.850 (67.3% and 90.1%) in the external validation set 2]. In the nested case-control study, this plsRglm model could detect the presence of preclinical ESCC with the AUC of 0.723, sensitivity of 54.2%, and specificity of 86.6%.

Our findings indicated that the plsRglm model based on four autoantibodies might help identify preclinical and early-stage ESCC.

The GRHL2 gene, encoding the Grainyhead-like 2 transcription factor, is essential for various biological processes. While GRHL2 has a complex role in cancer biology, its genetic variants have been also implicated in different forms of hearing loss (HL), including autosomal dominant non-syndromic hearing loss (DFNA28). Here, we report a novel c.1061C>T, p.(Ala354Val) mutation within the DNA binding domain (DBD) of GRHL2 that was identified in a three-generation HL family using a targeted multi-gene panel covering 237 HL-related genes. Unlike the previously reported DFNA28-causing variants that result in protein truncation, the impact of the p.(Ala354Val) missense change cannot be attributed to GRHL2 transcript level or composition, but to an alteration in protein function. Molecular dynamics simulations revealed destabilization of the p.(Ala354Val) mutant GRHL2 dimer interface and an altered DNA binding dynamics, leading to chaotic interaction patterns despite increased binding affinity to DNA. Functional assays demonstrated that the p.(Ala354Val) mutation and other DFNA28-related mutations in the DBD lead to loss of GRHL2 transcriptional transactivation activity, while the p.(Arg537Profs*11) mutation in the dimerization domain results in a gain-of-function effect. The findings indicate that both GRHL2 haploinsufficiency and gain-of-function contribute to HL and underscore the complex regulatory role of GRHL2 in maintaining proper function of the auditory system. Our study emphasizes the need to consider structural and functional aspects of gene variants to better understand their pathogenic potential. As GRHL2 is involved in a multitude of cellular processes, the data gathered here can be also applicable to other conditions.

The tumor suppressor p53 can trigger tumor resistance to chemotherapy by facilitating DNA damage repair and maintaining genomic integrity. Here, we report that a p53-induced circular RNA circASCC3 promotes chemotherapeutic resistance by resolving R-loops. Our results reveal that p53 directly activates the transcription of ASCC3, the host gene of circASCC3. In addition, the RNA-binding protein SFPQ is identified to inhibit the formation of circASCC3 by associating with its flanking regions. Importantly, p53 facilitates the formation of circASCC3 by repressing the expression of SFPQ. CircASCC3 has a marginal effect on the survival and growth of cancer cells under normal growing conditions but surprisingly boosts their survival and growth in response to DNA damage stress. Mechanistic analysis reveals that circASCC3 binds to the DEAD-box RNA helicase DDX5 to inhibit its proteasomal degradation. This results in the prevention of R-loop accumulation due to DNA damage, thereby conferring tumor resistance to chemotherapy. Together, our study uncovers that p53 activates circASCC3 to promote R-loop resolution, which maintains genomic stability and potentially contributes to chemoresistance.

Immune checkpoint inhibitors (CPIs) have revolutionized cancer therapy for several tumor indications. However, a substantial fraction of patients treated with CPIs derive no benefit or have short-lived responses to CPI therapy. Identifying patients who are most likely to benefit from CPIs and deciphering resistance mechanisms is therefore essential for developing adjunct treatments that can abrogate tumor resistance.

In this study, we used a machine learning approach that used the US-based nationwide de-identified Flatiron Health and Foundation Medicine non-small cell lung carcinoma (NSCLC) clinico-genomic database to identify genomic markers that predict clinical responses to CPI therapy. In total, we analyzed data from 4,433 patients with NSCLC.

Analysis of pretreatment genomic data from 1,511 patients with NSCLC identified. Of the 36 genomic signatures identified, 33 exhibited strong predictive capacity for CPI response (n=1150) compared with chemotherapy response (n=361), while three signatures were prognostic. These 36 genetic signatures had in common a core set of four genes (BRAF, BRIP1, FGF10, and FLT1). Interestingly, we observed that some (n=19) of the genes in the signatures (eg, TP53, EZH2, KEAP1 and FGFR2) had alternative mutations with contrasting clinical outcomes to CPI therapy. Finally, the genetic signatures revealed multiple biological pathways involved in CPI response, including MAPK, PDGF, IL-6 and EGFR signaling.

In summary, we found several genomic markers and pathways that provide insight into biological mechanisms affecting response to CPI therapy. The analyses identified novel targets and biomarkers that have the potential to provide candidates for combination therapies or patient enrichment strategies, which could increase response rates to CPI therapy in patients with NSCLC.

Li-Fraumeni syndrome (LFS) is a hereditary cancer predisposition syndrome associated with a highly penetrant cancer spectrum characterized by germline TP53 mutations. We characterized the first LFS zebrafish hotspot mutants, tp53 R217H and R242H (human R248H and R273H), and found these mutants exhibit partial-to-no activation of p53 target genes, have defective cell-cycle checkpoints, and display partial-to-full resistance to apoptosis, although the R217H mutation has hypomorphic characteristics. Spontaneous tumor development histologically resembling human sarcomas was observed as early as 6 months. tp53 R242H mutants had a higher lifetime tumor incidence compared to tp53 null and R217H mutants, suggesting it is a more aggressive mutation. We observed mutation-specific tumor phenotypes across tp53 mutants with associated diverse transcriptomic and DNA methylome profiles in tp53 mutant larvae, impacting metabolism, cell signalling, and biomacromolecule synthesis and degradation. These tp53 zebrafish mutants demonstrate fidelity to their human counterparts and provide new insights into underlying tumorigenesis mechanisms and kinetics that suggest metabolic rewiring and cellular signalling changes occur prior to tumor initiation, which will guide targeted therapeutics for LFS.

Gallbladder cancer (GBC) is the most common malignant tumor of the biliary tract and is often prone to early distant metastasis. However, the mechanisms underlying GBC's invasive metastasis remain unclear. This study identified that F-box only protein 33 (FBXO33) expression is significantly elevated in GBC and is negatively associated with patient prognosis. In vivo and in vitro experiments demonstrated that knockdown of FBXO33 inhibits epithelial-mesenchymal transition (EMT) progression in GBC, while overexpression of FBXO33 promotes EMT progression. Mechanistically, FBXO33 regulates EMT progression by modulating the polyubiquitination of p53 at K291 and K292. Moreover, the upregulation of FBXO33 in GBC is driven by transcriptional regulation mediated by Yin Yang-1 (YY1). The lactylation modification of YY1 at K183 was found to be essential for the transcriptional activation of FBXO33. These findings underscore the role of the lactylation-driven FBXO33-p53 axis in promoting the invasive metastasis of GBC.

Glioblastoma multiforme (GBM) is the most prevalent and aggressive primary brain tumor in adults, characterized by a poor prognosis and significant resistance to existing treatments. Despite progress in therapeutic strategies, the median overall survival remains approximately 15 months. A hallmark of GBM is its intricate molecular profile, driven by disruptions in multiple signaling pathways, including PI3K/AKT/mTOR, Wnt, NF-κB, and TGF-β, critical to tumor growth, invasion, and treatment resistance. This review examines the epidemiology, molecular mechanisms, and therapeutic prospects of targeting these pathways in GBM, highlighting recent insights into pathway interactions and discovering new therapeutic targets to improve patient outcomes.

TP53 mutations are linked to aggressive progression and chemoresistance in gastric cancer (GC). Frameshift mutation is the second most common mutation type of TP53. However, the consequences of this mutation type in GC were not well understood, and targeted therapies for cancer patients harboring frameshift mutations were also not established. Histone methylation significantly influences tumorigenesis in TP53-mutated cancers, and related inhibitors are emerging as specific therapeutic strategies.

By treating GC cell lines harboring various TP53 mutation types with a library of histone demethylase inhibitors, we identified that GSK690, a reversible inhibitor of lysine-specific demethylase 1 (LSD1), selectively inhibits GC cells harboring TP53 frameshift mutations without nuclear localization sequence (NLS) (termed TP53 Frameshift NLS), which accounts for 89% TP53 frameshift mutations in GC patients. GSK690 showed significant specific inhibition in vitro and in vivo against this subtype by inducing G1/S cell cycle arrest via the LSD1-CCNA2 axis. Importantly, dual-luciferase assays and ChIP-qPCR confirmed that the loss of transcriptional repression activities of p53 in drives LSD1 upregulation in TP53 Frameshift NLS cancer cells.

In summary, our results indicate that the nuclear localization deficiency of p53 accounts for increased expression of LSD1 in TP53 Frameshift NLS GCs. GSK690 inhibits cell cycle progression and tumor growth by suppressing aberrantly activated LSD1-CCNA2 signaling in this GC subtype, counteracting malignant proliferation and thereby providing a precise therapeutic strategy for GC patients with TP53 Frameshift NLS.

Globally, breast and ovarian cancers are major health concerns in women and account for significantly high cancer-related mortality rates. Dysregulations and mutations in genes like TP53, BRCA1/2, KRAS and PTEN increase susceptibility towards cancer. Here, we discuss the impact of mutations in the key regulatory gene, TP53 and polymorphisms in its negative regulator MDM2 which are reported to accelerate cancer progression. Missense mutations, null mutations, transversions, transitions, and point mutations occurring in the TP53 gene can cause an increase in metastatic activity. This review discusses mutations occurring in exon regions of TP53, polymorphisms in MDM2 and their interaction with large ribosomal subunit protein (RPL) leading to cancer development. We also highlight the potential of small molecules e.g. p53 activators like XI-011, Tenovin-1, and Nutlin-3a for the treatment of breast and ovarian cancers. The therapeutic efficacy of natural compounds in amelioration of these two types of cancers is also discussed.

Pancreatic intraepithelial neoplasia (PanIN) is the most common precursor lesion of pancreatic ductal adenocarcinoma (PDAC), which has poor prognosis with a short median overall survival of 6-12 months and a low 5-year survival rate of approximately 3%. It is crucial to remove PanIN lesions to prevent the development of invasive PDAC, as PDAC spreads rapidly outside the pancreas. This review aims to provide the latest knowledge on PanIN risk, pathology, cellular origin, genetic susceptibility, and diagnosis, while identifying research gaps that require further investigation in this understudied area of precancerous lesions. PanINs are classified into PanIN 1, PanIN 2, and PanIN 3, with PanIN 3 having the highest likelihood of developing into invasive PDAC. Differentiating between PanIN 2 and PanIN 3 is clinically significant. Genetic alterations found in PDAC are also present in PanIN and increase with the grade of PanIN. Imaging methods alone are insufficient for distinguishing PanIN, necessitating the use of genetic and molecular tests for identification. In addition, metabolomics technologies and miRNAs are playing an increasingly important role in the field of cancer diagnosis, offering more possibilities for efficient identification of PanIN. Although detecting and stratifying the risk of PanIN poses challenges, the combined utilization of imaging, genetics, and metabolomics holds promise for improving patient survival in this field.

There is intratumor heterogeneity in the stabilization of missense mutant p53, and it has been thought that only cells with nuclear accumulation of mutant p53 have oncogenic function. However, using mouse intestinal tumor-derived organoids, we show that mutant p53-stabilized cells transactivate Wnt/β-catenin signaling in neighboring p53-destabilized cells through activating the COX-2/PGE2 pathway. These results suggest that both p53-stabilized cells and p53-destabilized cells contribute to malignant progression through interaction within the intratumor microenvironment.

Background: Pancreatic Ductal Adeno-Carcinoma (PDAC) is a highly aggressive cancer, with limited treatment options. Disruption of the circadian clock, which regulates key cellular processes, has been implicated in PDAC initiation and progression. Hence, targeting circadian clock components may offer new therapeutic opportunities for the disease. This study investigates the cytopathic effects of TH301, a novel CRY2 stabilizer, on PDAC cells, aiming to evaluate its potential as a novel therapeutic agent. Methods: PDAC cell lines (AsPC-1, BxPC-3 and PANC-1) were treated with TH301, and cell viability, cell cycle progression, apoptosis, autophagy, circadian gene, and protein expression profiles were analyzed, using MTT assay, flow cytometry, Western blotting, and RT-qPCR technologies. Results: TH301 proved to significantly decrease cell viability and to induce cell cycle arrest at the G1-phase across all PDAC cell lines herein examined, especially the AsPC-1 and BxPC-3 ones. It caused dose-dependent apoptosis and autophagy, and it synergized with Chloroquine and Oxaliplatin to enhance anti-oncogenicity. The remarkable induction of p21 by TH301 was shown to follow clock- and p53-independent patterns, thereby indicating the critical engagement of alternative mechanisms. Conclusions: TH301 demonstrates significant anti-cancer activities in PDAC cells, thus serving as a promising new therapeutic agent, which can also synergize with approved treatment schemes by targeting pathways beyond circadian clock regulation. Altogether, TH301 likely opens new therapeutic windows for the successful management of pancreatic cancer in clinical practice.

The tumor secretome comprises the totality of protein factors secreted by various cell components within the tumor microenvironment, serving as the primary medium for signal transduction between tumor cells and between tumor cells and stromal cells. The deletion or mutation of the p53 gene leads to alterations in cellular secretion characteristics, contributing to the construction of the tumor microenvironment in a cell non-autonomous manner. This review discusses the critical roles of mutant p53 in regulating the tumor secretome to remodel the tumor microenvironment, drive tumor progression, and influence the plasticity of cancer-associated fibroblasts (CAFs) as well as the dynamics of tumor immunity by focusing on both secreted protein expression and secretion pathways. The aim is to provide new insights for targeted cancer therapies.

Background and Objectives: Temperature-sensitive (TS) mutants of TP53 are thermally unstable, unfolded, and inactive at body temperature but can be refolded and reactivated at sub-physiological temperatures. TS TP53 may be amenable for functional rescue by hypothermia or structure-stabilizing drugs, and may retain low-level transcriptional activity at 37 °C. TP53 mutations are observed in 47% of all esophageal cancers (ECs) and 25% to 40% of gastric cancers (GCs). We aimed to investigate the trends and outcomes of EC and GC with TS TP53 mutations using cBioportal. We hypothesize that TS TP53 mutants in EC and GC present a unique prognostic profile distinct from non-TS TP53 mutants, potentially affecting overall survival and cancer progression. Materials and Methods: We identified 1924 patients from cBioportal with GC or EC, harboring any TP53 mutation. Patients were then stratified based on the TP53 temperature sensitivity according to a recently reported functional analysis of its activity. Patients were also stratified based on a history of Barrett's esophagus (BE), cancer stage, sex, and race. We then compared populations (TS vs. non-TS TP53) to assess differences and evaluated survival outcomes. Results: Males represented 77% of the cohort, and 51.6% of the samples were from patients with stage IV cancer. No association was found between TS vs. non-TS mutational status and BE, cancer stage, or race. Interestingly, a significantly higher proportion of females (22.9%) than males (14.5%) displayed a TS TP53 mutation (p = 0.012). No significant difference was seen in overall survival between the TS and non-TS mutations capable of ≥50% growth suppression at 32 °C (median = 33 vs. 28 months, p = 0.36). This trend was also observed when the patients were filtered based on cancer location. The median survival for EC was 32.5 months compared to 33 months (p = 0.67). In cases of GC, median survival times could not be determined due to the insufficient number of events. Conclusions: Although no statistical significance was observed, a decrease in overall survival for patients with TS TP53 mutations was noted. The result is counterintuitive given that TS mutants have less severe structural destabilization and suggests TS TP53 mutations may have a unique prognostic value that warrants further investigation.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer death worldwide, and classifying the developmental stages of HCC can help with early prognosis and treatment. This study aimed to investigate diagnostic and prognostic molecular signatures underlying the progression of HCC, including tumor initiation and growth, and to classify its developmental stages based on gene expression levels. We integrated data from two cancer systems, including 78 patients with Edmondson-Steiner (ES) grade and 417 patients with TNM stage cancer. Functional profiling was performed using identified signatures. Using a multinomial logistic regression model (MLR), we classified controls, early-stage HCC, and advanced-stage HCC. The model was validated in three independent cohorts comprising 45 patients (neoplastic stage), 394 patients (ES grade), and 466 patients (TNM stage). Multivariate Cox regression was employed for HCC prognosis prediction. We identified 35 genes with gradual upregulation or downregulation in both ES grade and TNM stage patients during HCC progression. These genes are involved in cell division, chromosome segregation, and mitotic cytokinesis, promoting tumor cell proliferation through the mitotic cell cycle. The MLR model accurately differentiated controls, early-stage HCC, and advanced-stage HCC across multiple cancer systems, which was further validated in various independent cohorts. Survival analysis revealed a subset of five genes from TNM stage (HR: 3.27, p < 0.0001) and three genes from ES grade (HR: 7.56, p < 0.0001) that showed significant association with HCC prognosis. The identified molecular signature not only initiates tumorigenesis but also promotes HCC development. It has the potential to improve clinical diagnosis, prognosis, and therapeutic interventions for HCC. This study enhances our understanding of HCC progression and provides valuable insights for precision medicine approaches.

The TP53 gene encodes p53, a transcription factor involved in tumor suppression. However, TP53 also encodes other protein isoforms, some of which can disrupt the tumor suppressor functions of p53 even in the absence of TP53 mutations. In particular, elevated levels of the Δ133TP53 mRNA are detected in many cancer types and can be associated with poorer disease-free survival. We investigated the mechanisms of action of the two proteins translated from the Δ133TP53 mRNA: the Δ133p53α and Δ160p53α isoforms, both of which retain the oligomerization domain of p53. We discovered that the Δ133p53α and Δ160p53α isoforms adopt an altered conformation compared to full-length p53, exposing the PAb240 epitope (RHSVVV), which is inaccessible to the PAb240 antibody in the functional conformation of p53 (reactive to PAb1620). The Δ133p53α and/or Δ160p53α isoforms form hetero-oligomers with p53, regulating the stability, the conformation and the transcriptional activity of the p53 hetero-oligomers. Under basal conditions, Δ133p53α and Δ160p53α, in complex with p53, prevent proteasome-dependent degradation leading to the accumulation of PAb240 reactive Δ133p53α/Δ160p53α/p53 hetero-oligomers without increasing p53 transcriptional activity. Conversely, depletion of endogenous Δ133p53α isoforms in human fibroblasts is sufficient to restore p53 transcriptional activity, towards p53-target genes involved in cell cycle arrest. In the DNA damage response (DDR), PAb240 reactive Δ133p53α/Δ160p53α/p53 hetero-oligomers are highly phosphorylated at Ser15 compared to PAb1620-reactive p53 complexes devoid of Δ133p53α and Δ160p53α. This suggests that PAb240-reactive p53 hetero-oligomers integrate DNA damage signals. Δ133p53α accumulation is a late event in the DDR that depends on p53, but not on its transcriptional activation. The formation of Δ133p53α and p53 complexes increases at later DDR stages. We propose that Δ133p53α isoforms regulate p53 conformation as part of the normal p53 biology, modulating p53 activity and thereby adapting the cellular response to the cell signals.

TP53 is a tumor suppressor gene frequently mutated in human cancers and is generally associated with poor outcomes. TP53 mutations are found in approximately 5% to 10% of patients with de novo acute myeloid leukemia (AML), more frequently observed in elderly patients and those with therapy-related AML. Despite recent advances in molecular profiling and the emergence of targeted therapies, TP53-mutated AML remains a challenge to treat. Current treatment strategies, including conventional chemotherapy, hypomethylating agents, and venetoclax-based therapies, have shown limited efficacy in TP53-mutated AML, with low response rates and poor overall survival. Allogeneic hematopoietic stem cell transplantation is a potentially curative option; however, its efficacy in TP53-mutated AML depends on comorbid conditions and disease status at transplantation. Novel therapeutic modalities, including immune-based therapies, did show promise in early-phase studies but did not translate into effective therapies in randomized controlled trials. This review provides a comprehensive overview of TP53 mutations in AML, outcomes based on allelic burden, clinical implications, and therapeutic challenges.

The p53 protein, encoded by the TP53 gene, serves as a critical tumor suppressor, playing a vital role in maintaining genomic stability and regulating cellular responses to stress. Dysregulation of p53 is frequently observed in hematological malignancies, significantly impacting disease progression and patient outcomes. This review aims to examine the regulatory mechanisms of p53, the implications of TP53 mutations in various hematological cancers, and emerging therapeutic strategies targeting p53. We conducted a comprehensive literature review to synthesize recent findings related to p53's multifaceted role in hematologic cancers, focusing on its regulatory pathways and therapeutic potential. TP53 mutations in hematological malignancies often lead to treatment resistance and poor prognosis. Current therapeutic strategies, including p53 reactivation and gene therapy, show promise in improving treatment outcomes. Understanding the intricacies of p53 regulation and the consequences of its mutations is essential for developing effective diagnostic and therapeutic strategies in hematological malignancies, ultimately enhancing patient care and survival.

Epigenetic alterations in gene expression have been implicated in cancer development and tumor immune escape, with posttranslational histone or non-histone modifications representing attractive targets for disease surveillance and therapy. SET domain bifurcated 1 (SETDB1) is a histone lysine methyltransferase that reversibly catalyzes the di- and tri-methylation of histone 3 lysine 9 (H3K9) on euchromatin, inhibiting gene transcription within these regions and facilitating the switch from euchromatic to heterochromatic states. Emerging evidence suggests that SETDB1 amplification and aberrant activation are significantly associated with poor prognosis in hepatocellular carcinoma (HCC), and contribute to HCC development, immune escape, and immune checkpoint blockade (ICB) resistance. Here, we provide an updated overview of the cellular and molecular effects of SETDB1 activity in hepatocarcinogenesis and progression and focus on studies linking its function to immunotherapy for HCC, and present current challenges and future perspectives for targeting SETDB1 in HCC treatment.

ERP29 gene encodes a chaperone protein critical for protein folding and secretion. Previous study linked ERP29 inhibition to an elevated risk of pharynx squamous cell carcinoma (PSCC) and reduced patients' survival. However, ERP29 role in PSCC progression remains unknown. Here, we investigated ERP29 impact on PSCC progression in cisplatin (CDDP)-sensitive (FaDu and LAU-2063), CDDP-treated (FaDu-CDDP), and CDDP-resistant (FaDu-R) cells. ERP29 silencing decreased necrosis and increased migration in CDDP-sensitive, treated, and resistant cells; and reduced E-cadherin and increased vimentin immunoexpression in CDDP-sensitive 3D-spheroids. During CDDP treatment, ERP29 silencing enhanced proliferation. In CDDP-sensitive cells, ERP29 silencing upregulated genes associated with WNT, MAPK, and PI3K/AKT signaling pathways while downregulating CASP9 expression. During CDDP treatment, ERP29 silencing downregulated MDM2 and CASP9 expression. In CDDP-resistant cells, ERP29 silencing upregulated SOS1, MAPK1, AKT1, ITGAV, and CCNE1, while downregulating KRAS, JUN, MDM2, and CASP9 expression. In addition, inhibition of microRNA miR-4421 increased ERP29 expression and decreased MAPK1, AKT1, and JUN expression in CDDP-sensitive cells, as well as SOS1, MAPK1, AKT1, and ITGAV in CDDP-resistant cells. Lower ERP29 and higher miR-4421 expressions were predictive of poor survival, suggesting a potential therapeutic use for miR-4421 inhibitors. Upon validation, these findings may contribute to targeted therapies for PSCC based on ensuring ERP29 expression.

Certain mutations can confer neomorphic gain of function (GOF) activities to the p53 protein that affect cancer progression. Yet the concept of mutant p53 GOF has been challenged. Here, using various strategies to alter the status of mutant versions of p53 in different cell lines, we demonstrate that mutant p53 stimulates cancer cell invasion in three-dimensional environments. Mechanistically, mutant p53 enhances RhoA/ROCK-dependent cell contractility and cell-mediated extracellular matrix (ECM) re-organization via increasing mevalonate pathway-dependent RhoA localization to the membrane. In line with this, RhoA-dependent pro-invasive activity is also mediated by IDI-1, a mevalonate pathway product. Further, the invasion-enhancing effect of mutant p53 is dictated by the biomechanical properties of the surrounding ECM, thereby adding a cell-independent layer of regulation to mutant p53 GOF activity that is mediated by dynamic reciprocal cell-ECM interactions. Together our findings link mutant p53 metabolic GOF activity with an invasive cellular phenotype in physiologically relevant and context-dependent settings.

This study addresses the contribution of mutant p53 to the process of cancer cell dissemination in physiologically relevant three-dimensional environments - a key characteristic of metastatic disease. Several mutant p53 proteins display pro-oncogenic activity with respect to cancer cell invasion in 3D environments via mevalonate pathway-dependent Rho/ROCK signaling axis.

The aim of this study is to explore the effects and specific mechanisms of heparanase on angiogenesis and iron deficiency anemia in TP53 mutant cancer. For this purpose, we conducted in vitro cell experiments and in vivo animal experiments respectively. In this study, we first analyzed the differential expression of heparanase in TP53 wild-type and mutant cells, and analyzed its effects on iron removal and angiogenesis in two types of CALU-1 and NCI-H358 cells. Secondly, we validated whether the mechanism of action of heparanase on TP53 mutant cells for iron removal and angiogenesis is related to VEGF. We applied the iron removal agonist erastin and VEGF inhibitor bevacizumab in both in vitro and in vivo experiments to validate the relationship between heparanase and VEGF in the mechanisms of iron removal and angiogenesis. The experimental results show that heparanase is highly expressed in TP53 mutated cancer cells, and has anti-ferroptosis and pro-angiogenic effects. Our experiment also confirmed that the effect of heparanase on TP53 mutant cancer's iron removal and angiogenesis is related to VEGF. In short, heparanase is highly expressed in p53 mutated lung cancer, and the mechanism of ferroptosis tolerance to TP53 mutated cancer is related to VEGF.

High Grade Serous Ovarian Cancer (HG-SOC), the most prevalent and aggressive gynecological malignancy, is marked by ubiquitous loss of functional p53, largely due to point mutations that arise very early in carcinogenesis. These mutations often lead to p53 protein misfolding and subsequent aggregation, yet the alterations in intracellular p53 dynamics throughout ovarian cancer progression remain poorly understood. HG-SOC originates from the fallopian tube epithelium, with a well-documented stepwise progression beginning with early pre-malignant p53 signatures. These signatures represent largely normal cells that express and accumulate mutant p53, which then transform into benign serous tubal intraepithelial lesions (STIL), progress into late pre-malignant serous tubal intraepithelial carcinoma (STIC), and ultimately lead to HGSOC. Here, we show that the transition from folded, soluble to aggregated mutant p53 occurs during the malignant transformation of benign precursor lesions into HGSOC. We analyzed fallopian tube tissue collected from ten salpingo-oophorectomy cases and determined the proportion of cells carrying soluble versus mis-folded/mutant p53 through conformation-sensitive staining and quantification. Misfolded p53 protein, prone to aggregation, is present in STICs and HG-SOCs, but notably absent from preneoplastic lesions and surrounding healthy tissue. Overall, our results indicate that aggregation of mutant p53 is a structural defect that distinguishes preneoplastic early lesions from late premalignant and malignant ones, offering a potential treatment window for targeting p53 aggregation and halting ovarian cancer progression.

Disease progression is a major problem in ovarian cancer. There are very few treatment options for patients with platinum-resistant ovarian cancer (PROC), and therefore, these patients have a particularly poor prognosis. The aim of the present study was to identify markers for monitoring the response of 123 PROC patients enrolled in the Phase I/II GANNET53 clinical trial, which evaluated the efficacy of Ganetespib in combination with standard chemotherapy versus standard chemotherapy alone. In total, 474 blood samples were collected, comprising baseline samples taken before the first administration of the study drugs and serial samples taken during treatment until further disease progression (PD). After microfluidic enrichment, 27 gene transcripts were analyzed using quantitative polymerase chain reaction and their utility for disease monitoring was evaluated. At baseline, ERCC1 was associated with an increased risk of PD (hazard ratio [HR] 1.75, 95% confidence interval [CI]: 1.20-2.55; p = 0.005), while baseline CDH1 and ESR1 may have a risk-reducing effect (CDH1 HR 0.66, 95% CI: 0.46-0.96; p = 0.024; ESR1 HR 0.58, 95% CI: 0.39-0.86; p = 0.002). ERCC1 was observed significantly more often (72.7% vs. 53.9%; p = 0.032) and ESR1 significantly less frequently (59.1% vs. 78.3%; p = 0.018) in blood samples taken at radiologically confirmed PD than at controlled disease. At any time during treatment, ERCC1-presence and ESR1-absence were associated with short PFS and with higher odds of PD within 6 months (odds ratio 12.77, 95% CI: 4.08-39.97; p < 0.001). Our study demonstrates the clinical relevance of ESR1 and ERCC1 and may encourage the analysis of liquid biopsy samples for the management of PROC patients.

Hepatocellular carcinoma (HCC), ranking as the second-leading cause of global mortality among malignancies, poses a substantial burden on public health worldwide. Anoikis, a type of programmed cell death, serves as a barrier against the dissemination of cancer cells to distant organs, thereby constraining the progression of cancer. Nevertheless, the mechanism of genes related to anoikis in HCC is yet to be elucidated.

This paper's data (TCGA-HCC) were retrieved from the database of the Cancer Genome Atlas (TCGA). Differential gene expression with prognostic implications for anoikis was identified by performing both the univariate Cox and differential expression analyses. Through unsupervised cluster analysis, we clustered the samples according to these DEGs. By employing the least absolute shrinkage and selection operator Cox regression analysis (CRA), a clinical predictive gene signature was generated from the DEGs. The Cell-Type Identification by Estimating Relative Subsets of RNA Transcripts (CIBERSORT) algorithm was used to determine the proportions of immune cell types. The external validation data (GSE76427) were procured from Gene Expression Omnibus (GEO) to verify the performance of the clinical prognosis gene signature. Western blotting and immunohistochemistry (IHC) analysis confirmed the expression of risk genes.

In total, 23 prognostic DEGs were identified. Based on these 23 DEGs, the samples were categorized into four distinct subgroups (clusters 1, 2, 3, and 4). In addition, a clinical predictive gene signature was constructed utilizing ETV4, PBK, and SLC2A1. The gene signature efficiently distinguished individuals into two risk groups, specifically low and high, demonstrating markedly higher survival rates in the former group. Significant correlations were observed between the expression of these risk genes and a variety of immune cells. Moreover, the outcomes from the validation cohort analysis aligned consistently with those obtained from the training cohort analysis. The results of Western blotting and IHC showed that ETV4, PBK, and SLC2A1 were upregulated in HCC samples.

The outcomes of this paper underscore the effectiveness of the clinical prognostic gene signature, established utilizing anoikis-related genes, in accurately stratifying patients. This signature holds promise in advancing the development of personalized therapy for HCC.

Mutation of thetumor suppressor gene, TP53 (tumor protein 53), occurs in up to 15% of all patients with acute myeloid leukemia (AML) and is enriched within specific clinical subsets, most notably in older adults, and including secondary AML cases arising from preceding myeloproliferative neoplasm (MPN), myelodysplastic syndrome (MDS), patients exposed to prior DNA-damaging, cytotoxic therapies. In all cases, these tumors have remained difficult to effectively treat with conventional therapeutic regimens. Newer approaches fortreatmentofTP53-mutated AML have shifted to interventions that maymodulateTP53 function, target downstream molecular vulnerabilities, target non-p53 dependent molecular pathways, and/or elicit immunogenic responses. This review will describe the basic biology of TP53, the clinical and biological patterns of TP53 within myeloid neoplasms with a focus on elderly AML patients and will summarize newer therapeutic strategies and current clinical trials.

Fludioxonil, an antifungal agent used as a pesticide, leaves a measurable residue in fruits and vegetables. It has been identified to cause endocrine disruption, interrupt normal development, and cause various diseases such as cancers. In this study, fludioxonil was examined for its effects on the development and metastasis of breast cancer cells. On fludioxonil exposure (10-5 M) for 72 h, mutant p53 (mutp53) MDA-MB-231 triple-negative breast cancer (TNBC) cells significantly inhibited cell viability and developed into polyploid giant cancer cells (PGCCs), with an increase in the number of nuclei and expansion in the cell body size. Fludioxonil exposure disrupted the normal cell cycle phase ratio, resulting in a new peak. In addition, PGCCs showed greater motility than the control and were resistant to anticancer drugs, i.e., doxorubicin, cisplatin, and 5-fluorouracil. Cyclin E1, nuclear factor kappa B (NF-κB), and p53 expressions were remarkably increased, and the expression of cell cycle-, epithelial-mesenchymal-transition (EMT)-, and cancer stemness-related proteins were increased in the PGCCs. The daughter cells obtained from PGCCs had the single nucleus but maintained their enlarged cell size and showed greater cell migration ability and resistance to the anticancer agents. Consequently, fludioxonil accumulated Cyclin E1 and promoted the inflammatory cytokine-enriched microenvironment through the up-regulation of TNF and NF-κB which led to the transformation to PGCCs via abnormal cell cycles such as mitotic delay and mitotic slippage in mutp53 TNBC MDA-MB-231 cells. PGCCs and their daughter cells exhibited significant migration ability, chemo-resistance, and cancer stemness. These results strongly suggest that fludioxonil, as an inducer of potential genotoxicity, may induce the formation of PGCCs, leading to the formation of metastatic and stem cell-like breast cancer cells.

It is believed that loss of p53 function plays a crucial role in the progression of well to poorly differentiated thyroid cancers including anaplastic thyroid carcinoma (ATC). Given the poor prognosis of ATC due to its strong therapeutic resistance, there is a need to establish new therapeutic targets to extend the survival of ATC patients. Activating transcription factor 3 (ATF3) can inhibit the oncogenic activity of mutant p53 and, as a result, contribute to tumor suppression in several TP53-mutated cancers. Herein, we demonstrate that the ectopic overexpression of ATF3 leads to the suppression of oncogenic mutant p53 activity in chemo-resistant 8305 C thyroid cancer cells harboring R273C p53 gene mutation.

The biological behavior of 8305 C cells was assessed pre- and post-transfection with pCMV6-ATF3 plasmid using MTT assay, fluorescent microscopy, cell cycle, and annexin V/PI flow cytometric analysis. The effect of ectopic ATF3 overexpression on the cellular level of p53 was examined by western blotting assay. The mRNA expression levels of TP53, TAp63, ΔNp63, and SHARP1 were evaluated in ectopic ATF3-expressing cells compared to controls.

The overexpression of ATF3 in 8305 C thyroid cancer cells significantly decreased cell viability and induced apoptosis and cell cycle arrest in vitro. The immunoblotting of p53 protein revealed that ATF3 overexpression significantly increased the level of mutant p53 in 8305C cells compared to mock-transfected control cells. Additionally, elevated mRNA levels of TAp63 and SHARP1 and a decreased mRNA level of ΔNp63 were observed in PCMV6-AC-ATF3-transfected 8305 C cells with significant differences compared to the mock and untreated cells.

In light of our findings, it is evident that therapeutic strategies aimed at increasing ATF3 expression or enhancing the interaction between ATF3 and mutant p53 can be a promising approach for the treatment of p53-mutated metastatic thyroid cancer.

Aggressive breast cancers harbor TP53 missense mutations. Tumor cells with TP53 missense mutations exhibit enhanced growth and survival through transcriptional rewiring. To delineate how TP53 mutations in breast cancer contribute to tumorigenesis and progression in vivo, we created a somatic mouse model driven by mammary epithelial cell-specific expression of Trp53 mutations. Mice developed primary mammary tumors reflecting the human molecular subtypes of luminal A, luminal B, HER2-enriched, and triple-negative breast cancer with metastases. Transcriptomic analyses comparing MaPR172H/- or MaPR245W/- mammary tumors to MaP-/- tumors revealed (1) differences in cancer-associated pathways activated in both p53 mutants and (2) Nr5a2 as a novel transcriptional mediator of distinct pathways in p53 mutants. Meta-analyses of human breast tumors corroborated these results. In vitro assays demonstrate mutant p53 upregulates specific target genes that are enriched for Nr5a2 response elements in their promoters. Co-immunoprecipitation studies revealed p53R172H and p53R245W interact with Nr5a2. These findings implicate NR5A2 as a novel mediator of mutant p53 transcriptional activity in breast cancer.

Our findings implicate NR5A2 as a novel mediator of mutant p53 transcriptional activity in breast cancer. NR5A2 may be an important therapeutic target in hard-to-treat breast cancers such as endocrine-resistant tumors and metastatic triple-negative breast cancers harboring TP53 missense mutations.

The incidence of vulvar carcinoma varies by race; however, it is a rare disease, and its genomic profiles remain largely unknown. This study examined the characteristics of vulvar squamous cell carcinoma (VSCC) in Japanese patients, focusing on genomic profiles and potential racial disparities. The study included two Japanese groups: the National Cancer Center Hospital (NCCH) group comprised 19 patients diagnosed between 2015 and 2023, and the Center for Cancer Genomics and Advanced Therapeutics group comprised 29 patients diagnosed between 2019 and 2022. Somatic mutations were identified by targeted or panel sequencing, and TP53 was identified as the most common mutation (52-81%), followed by HRAS (7-26%), CDKN2A (21-24%), and PIK3CA (5-10%). The mutation frequencies, except for TP53, were similar to those of Caucasian cohorts. In the NCCH group, 16 patients of HPV-independent tumors were identified by immunohistochemistry and genotyping. Univariate analysis revealed that TP53-mutated patients were associated with a poor prognosis (log-rank test, P = 0.089). Japanese VSCC mutations resembled those of Caucasian vulvar carcinomas, and TP53 mutations predicted prognosis regardless of ethnicity. The present findings suggest potential molecular-targeted therapies for select VSCC patients.

The three-dimensional structure of proteins determines their function in vital biological processes. Thus, when the structure is known, the molecular mechanism of protein function can be understood in more detail and obtained information utilized in biotechnological, diagnostics, and therapeutic applications. Over the past five years, machine learning (ML)-based modeling has pushed protein structure prediction to the next level with AlphaFold in the front line, predicting the structure for hundreds of millions of proteins. Further advances recently report promising ML-based approaches for solving remaining challenges by incorporating functionally important metals, co-factors, post-translational modifications, structural dynamics, and interdomain and multimer interactions in the structure prediction process.

Molecular profiling studies have shed new light on the complex biology of prostate cancer. Genomic studies have highlighted that structural rearrangements are among the most common recurrent alterations. In addition, both germline and somatic mutations in DNA repair genes are enriched in patients with advanced disease. Primary prostate cancer has long been known to be multifocal, but recent studies demonstrate that a large fraction of prostate cancer shows evidence of multiclonality, suggesting that genetically distinct, independently arising tumor clones coexist. Metastatic prostate cancer shows a high level of morphologic and molecular diversity, which is associated with resistance to systemic therapies. The resulting high level of intratumoral heterogeneity has important implications for diagnosis and poses major challenges for the implementation of molecular studies. Here we provide a concise review of the molecular pathology of prostate cancer, highlight clinically relevant alterations, and discuss opportunities for molecular testing.

Deficiency of citrin, the liver-type aspartate-glutamate carrier, arises from biallelic mutations of the gene SLC25A13. Although citrin deficiency (CD) is associated with higher risk of hepatocellular carcinoma (HCC) in adult patients, this association remains inconclusive in pediatric cases. The patient in this paper had been diagnosed to have CD by SLC25A13 analysis at the age 10 months, and then in response to dietary therapy, her prolonged jaundice and marked hepatosplenomegaly resolved gradually. However, she was referred to the hospital once again due to recurrent abdominal distention for 2 weeks at her age 4 years and 9 months, when prominently enlarged liver and spleen were palpated, along with a strikingly elevated serum alpha-fetoprotein (AFP) level of 27605 ng/mL as well as a large mass in the right liver lobe and a suspected tumor thrombus within the portal vein on enhanced computed tomography. After 4 rounds of adjuvant chemotherapy, right hepatic lobectomy and portal venous embolectomy were performed at her age 5 years and 3 months, and metastatic hepatoblastoma was confirmed by histopathological analysis. Afterwards, the patient underwent 5 additional cycles of chemotherapy and her condition remained stable for 7 months after surgery. Unfortunately, hepatoblastoma recurred in the left lobe at the age 5 years and 10 months, which progressed rapidly into liver failure, and led to death at the age 6 years and 1 month. As far as we know, this is the the first case of hepatoblastoma in a patient with CD, raising the possibility of an association between these two conditions.

The diheteroarylamide-based compound 1C8 and the aminothiazole carboxamide-related compound GPS167 inhibit the CLK kinases, and affect the proliferation of a broad range of cancer cell lines. A chemogenomic screen previously performed with GPS167 revealed that the depletion of components associated with mitotic spindle assembly altered sensitivity to GPS167. Here, a similar screen performed with 1C8 also established the impact of components involved in mitotic spindle assembly. Accordingly, transcriptome analyses of cells treated with 1C8 and GPS167 indicated that the expression and RNA splicing of transcripts encoding mitotic spindle assembly components were affected. The functional relevance of the microtubule connection was confirmed by showing that subtoxic concentrations of drugs affecting mitotic spindle assembly increased sensitivity to GPS167. 1C8 and GPS167 impacted the expression and splicing of transcripts in pathways relevant to tumor progression, including MYC targets and the epithelial mesenchymal transition (EMT). Finally, 1C8 and GPS167 altered the expression and alternative splicing of transcripts involved in the antiviral immune response. Consistent with this observation, depleting the double-stranded RNA sensor DHX33 suppressed GPS167-mediated cytotoxicity on HCT116 cells. Our study uncovered molecular mechanisms through which 1C8 and GPS167 affect cancer cell proliferation as well as processes critical for metastasis.