Advances in pancreatic cancer epigenetics: From the mechanism to the clinic

Table 1 Epigenetic characteristics of pancreatic cancer

Epigenetic mechanism	Key changes	Genes affected	Role in pancreatic cancer
DNA methylation	Hypermethylation of tumor suppressor genes, particularly in the promoter regions	p16, BRCA1, RASSF1A, CDKN2A, APC	DNA hypermethylation in the promoter regions of tumor suppressor genes (e.g., p16 and BRCA1) silences their expression, allowing for uncontrolled cell division, which leads to cancer initiation and progression. Methylation of CDKN2A and RASSF1A contributes to tumor resistance and poor prognosis
Histone modifications	Histone acetylation (activation) and deacetylation (silencing)	p21, p53, H3K9me, H3K27me, HDACs	Histone acetylation (activation) and deacetylation (silencing) affect the accessibility of DNA. In pancreatic cancer, HDACs are overexpressed, leading to silencing of tumor suppressor genes like p21 and p53, which promotes cell cycle dysregulation and tumor progression
Noncoding RNAs (miRNAs and lncRNAs)	Dysregulated expression of miRNAs and lncRNAs that impact tumor behavior	miR-21, miR-155, HOTAIR, MALAT1	Upregulation of miRNAs (e.g., miR-21 and miR-155) and lncRNAs (e.g., MALAT1 and HOTAIR) suppress tumor suppressor genes, promoting cancer cell proliferation, invasiveness, and metastasis by modulating gene expression
Chromatin remodeling	ATP-dependent chromatin remodeling complexes change chromatin structure, affecting gene transcription	SWI/SNF complex, BRG1	ATP-dependent chromatin remodeling complexes like SWI/SNF and BRG1 modify chromatin structure, making genes more or less accessible for transcription. In pancreatic cancer, the dysfunction or downregulation of these complexes leads to silencing of tumor suppressor genes, promoting cancer progression and metastasis

lncRNA: Long noncoding RNA.

Table 2 Epigenetic markers for early diagnosis in pancreatic cancer

Epigenetic marker	Description	Stage sensitivity (%)	Sensitivity (%)
BNC1 methylation	Methylation of BNC1 in blood differentiates early-stage pancreatic cancer from healthy individuals	Stage I: 62.5%, Stage II: 65%, Stage III/IV: 100%	100% in Stage I, 88.9% in Stage IIA, 100% in Stage IIB
ADAMTS1 methylation	Methylation of ADAMTS1 in blood has high sensitivity and specificity for early diagnosis of pancreatic cancer	Stage I/II: 87.2%, Stage I/II: 95.8%	87.2% sensitivity, 95.8% specificity
GATA4 methylation	GATA4 methylation is associated with early diagnosis and prognosis of pancreatic cancer	High sensitivity and specificity for early diagnosis	High specificity for early detection
SFRP1 methylation	SFRP1 methylation is predictive of malignancy risk in pancreatic cancer and detected in pancreatic juice/blood	High sensitivity in pancreatic juice, predictive of malignancy risk	Widely detected in blood samples
miR-181b	miR-181b expression levels correlate with pancreatic cancer stages	MiR-196a, MiR-210 combined with CA19-9 improves accuracy	Improved staging accuracy with miR-196a and miR-210 detection
miR-196a	miR-196a expression levels correlate with pancreatic cancer stages, combined detection with CA19-9 improves staging accuracy	MiR-196a, MiR-210 combined with CA19-9 improves accuracy	Improved staging accuracy with miR-196a and miR-210 detection
miR-210	miR-210 expression levels correlate with pancreatic cancer stages, combined detection with CA19-9 improves staging accuracy	HOTAIR correlates with early diagnosis, found in saliva and blood	Effective early detection in pancreatic cancer patients
HOTAIR (lncRNA)	Overexpression of HOTAIR correlates with early onset and malignancy of pancreatic tumors	miR-210 and miR-196a combined with CA19-9 improve accuracy	Effective for early detection and staging

lncRNA: Long noncoding RNA.

Table 3 Epigenetic markers in prognosis evaluation

Epigenetic marker	Description	Association with prognosis	Potential for use
MET hypomethylation	Hypomethylation of MET and ITGA2 correlates with high gene expression, associated with lower survival rates	High expression correlated with low survival rates	Useful in prognostic evaluation, treatment monitoring
ITGA2 hypomethylation	Methylation of the SFRP1 promoter serves as a prognostic and predictive biomarker in pancreatic cancer	Predicted poor prognosis and potential recurrence	Useful as a blood biomarker for stage III or IV pancreatic cancer
CDKN2A methylation	Methylation of CDKN2A promotes tumor initiation and metastasis, correlating with poor prognosis	Strong correlation with cell cycle dysregulation, leading to metastasis	Can be used for monitoring prognosis and recurrence
SFRP1 methylation	Methylation of SFRP1 has high specificity for advanced pancreatic cancer, correlating with poor prognosis	A predictive blood biomarker for stage III or IV pancreatic cancer	Potential blood biomarker for pancreatic cancer diagnosis
NPTX2 methylation	NPTX2 methylation in cfDNA correlates with poor prognosis and overall survival prediction	Associated with poor prognosis and treatment response	Non-invasive blood biomarker for prognosis and monitoring
HOTAIR (lncRNA)	HOTAIR overexpression in advanced cancer stages correlates with poor survival and advanced tumor stages	High expression linked to low survival, particularly in late-stage cancer	Useful for determining survival potential in late cancer stages
circFARP1	High expression of circFARP1 in serum correlates with lower survival rates in pancreatic cancer	High levels in serum linked to poor survival rates	Potential prognostic marker in serum for advanced PDAC
miR-196a	High expression of miR-196a is associated with lower survival rates and poor prognosis	Associated with poor prognosis, affects metastasis	Associated with better survival outcomes, useful in treatment
miR-210	High expression of miR-210 correlates with improved survival rates in pancreatic cancer patients	Correlated with improved survival rates in pancreatic cancer	May help predict the prognosis and overall survival
miR-124	Low expression of miR-124 is associated with metastasis and poor prognosis	Low miR-124 expression correlated with metastasis and reduced survival	Potential prognostic marker for cancer invasiveness

PDAC: Pancreatic ductal adenocarcinoma; lncRNA: Long noncoding RNA.

Table 4 Epigenetic markers in treatment response monitoring

Epigenetic marker	Description	Impact on treatment response	Clinical relevance
SFRP1 methylation	Methylation of SFRP1 promoter is associated with poor treatment response and resistance to gemcitabine	Increased SFRP1 methylation linked to reduced sensitivity to chemotherapy drugs like gemcitabine	Potential biomarker for assessing chemotherapy resistance, especially in advanced PDAC
circFARP1	CircFARP1 is a CAF-specific circRNA positively correlated with gemcitabine resistance	Gemcitabine resistance observed in patients with high circFARP1 expression	Could guide personalized treatment strategies for patients showing gemcitabine resistance
circBIRC6	CircBIRC6, upregulated in CAF-derived EVs, correlates with oxaliplatin chemotherapy resistance	CircBIRC6 contributes to resistance against chemotherapy, especially oxaliplatin	Marker for predicting oxaliplatin resistance and helping in therapeutic planning
HOTAIR (lncRNA)	HOTAIR overexpression is linked to poor survival and chemotherapy resistance in advanced cancer stages	High expression correlates with poor response to therapy, particularly in advanced stages	Can be used to predict response to therapy in advanced pancreatic cancer
circFARP1 (hsa_circ_0002557)	High circFARP1 levels correlate with gemcitabine resistance and lower survival in advanced PDAC	CircFARP1 Levels predict resistance to gemcitabine and poor survival	Indicates poor prognosis, guiding clinicians in optimizing chemotherapy strategies
EZH2 (Histone Methyltransferase)	EZH2 overexpression in pancreatic cancer cells leads to chemotherapy resistance	EZH2 overexpression contributes to pancreatic cancer resistance to chemotherapy	Targeting EZH2 could enhance the efficacy of current chemotherapies.
HDAC1 & PRMT1	HDAC1 and PRMT1 are epigenetic regulators influencing drug resistance by modifying chromatin and gene expression	HDAC1 and PRMT1 modulation affect tumor cell resistance to chemotherapy and immunotherapy	Both are crucial in predicting and overcoming drug resistance in pancreatic cancer patients

PDAC: Pancreatic ductal adenocarcinoma; lncRNA: Long noncoding RNA.

Table 5 Epigenetic therapeutic strategies in pancreatic cancer

Strategy	Targeted epigenetic mechanism	Therapeutic agents	Studies/efficacy
DNA demethylation	DNA methylation	5-Azacytidine (5-Aza), Decitabine	Used to restore silenced tumor suppressor genes. Clinical trials have shown limited success in PDAC
Histone deacetylation inhibition	Histone modification	Vorinostat, Romidepsin	Inhibits HDACs, leading to tumor suppressor gene activation and reduced tumor growth. Promising in early trials
miRNA therapy	Noncoding RNA	ExomiR-34a (miR-34a encapsulated in exosomes)	ExomiR-34a showed suppression of pancreatic cancer cell growth and induced apoptosis in preclinical trials
lncRNA modulation	Noncoding RNA	Antisense oligonucleotides, RNAi	Targets lncRNAs to reverse drug resistance and regulate oncogenes. Emerging as a promising approach
CRISPR/Cas13 for lncRNA	Noncoding RNA	CRISPR-Cas13	Modulates lncRNAs to target pancreatic cancer growth and metastasis. Still in preclinical stages
Combination therapy with immunotherapy	Epigenetic Modifications & Immunotherapy	HDAC inhibitors + PD-1/PD-L1 inhibitors	Epigenetic inhibitors combined with immune checkpoint inhibitors showed potential in enhancing immune responses

PDAC: Pancreatic ductal adenocarcinoma; lncRNA: Long noncoding RNA.