Chen YZ, Liu J, Wang YP, Du J, Ma JC, Jin GS. EPZ020411, a PRMT6 inhibitor, suppresses colorectal cancer cell proliferation, migration, and invasion through targeting the TGM2/MAPK axis. World J Gastrointest Oncol 2026; 18(9): 123745 [DOI: 10.4251/wjgo.123745]
Corresponding Author of This Article
Gong-Sheng Jin, MD, Department of Surgical Oncology, The First Affiliated Hospital of Bengbu Medical University, No. 287 Changhuai Street, Longzihu District, Bengbu 233000, Anhui Province, China. jgs2007@qq.com
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Gastroenterology & Hepatology
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research-article
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Chen YZ, Liu J, Wang YP, Du J, Ma JC, Jin GS. EPZ020411, a PRMT6 inhibitor, suppresses colorectal cancer cell proliferation, migration, and invasion through targeting the TGM2/MAPK axis. World J Gastrointest Oncol 2026; 18(9): 123745 [DOI: 10.4251/wjgo.123745]
World J Gastrointest Oncol. Sep 15, 2026; 18(9): 123745 Published online Sep 15, 2026. doi: 10.4251/wjgo.123745
EPZ020411, a PRMT6 inhibitor, suppresses colorectal cancer cell proliferation, migration, and invasion through targeting the TGM2/MAPK axis
Yu-Zhong Chen, Jia Liu, Ya-Ping Wang, Jun Du, Jia-Chi Ma, Gong-Sheng Jin
Yu-Zhong Chen, Jia Liu, Jun Du, Jia-Chi Ma, Gong-Sheng Jin, Department of Surgical Oncology, The First Affiliated Hospital of Bengbu Medical University, Bengbu 233000, Anhui Province, China
Ya-Ping Wang, Department of Medical Oncology, The First Affiliated Hospital of Bengbu Medical University, Bengbu 233000, Anhui Province, China
Author contributions: Ma JC and Jin GS designed the project ideas, offered crucial guidance, revised the manuscript, and reviewed it to ensure adherence to ethical and scientific rigor; Chen YZ and Liu J designed and conducted experiments, wrote the manuscript, prepared experimental materials for the study, and participated in data interpretation, prepared Figures 1-5; Wang YP and Du J mainly participated in data collection, data analysis and data interpretation, and prepared Figure 6.
AI contribution statement: AI tools (specifically ChatGPT) were used solely for linguistic refinement and formatting assistance. No AI tool was involved in the generation of research data, interpretation of results, or formulation of conclusions. All AI-generated outputs were critically reviewed and revised by the authors.
Supported by Anhui Provincial University Scientific Research Project, No. 2023AH051989; Anhui Provincial Department of Education Faculty Development Program for Early- and Mid-Career Academics, No. JWFX2024022; Doctoral Research Start-Up Fund of the First Affiliated Hospital of Bengbu Medical University, No. 2024-CYZ.
Institutional animal care and use committee statement: All procedures involving animals were reviewed and approved by the Ethics Committee of the Laboratory Animal Center of Bengbu Medical University (approval No. 2024-344).
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Data sharing statement: All data generated or analyzed during this study are included in this published article.
Corresponding author: Gong-Sheng Jin, MD, Department of Surgical Oncology, The First Affiliated Hospital of Bengbu Medical University, No. 287 Changhuai Street, Longzihu District, Bengbu 233000, Anhui Province, China. jgs2007@qq.com
Received: June 2, 2026 Revised: July 7, 2026 Accepted: August 25, 2026 Published online: September 15, 2026 Processing time: 98 Days and 22.6 Hours
Abstract
BACKGROUND
Colorectal cancer (CRC) remains a highly fatal cancer worldwide, while metastasis is the main challenge in clinical treatment. Protein arginine methyltransferase 6 (PRMT6), a type I PRMT family member, catalyzes asymmetric methylation of arginine residues and contributes to tumor cell proliferation, invasion, metastasis and chemoresistance by both epigenetic and post-translational mechanisms. Notably, PRMT6 is overexpressed in CRC tissues and is associated with a poor survival outcome for patients. However, its targeted therapy and related mechanisms remain unclear.
AIM
To investigate the antitumor activity and molecular mechanisms of EPZ020411 in CRC HCT116 and CACO-2 cells.
METHODS
Human CRC cell lines (HCT116 and CACO-2) were treated with EPZ020411, and cell proliferation, migration and invasion were evaluated by CCK-8, EdU, colony formation, wound healing and Transwell assays. RNA sequencing was performed to screen differentially expressed genes, and the results were validated by reverse transcription-quantitative polymerase chain reaction and western blotting. To assess the functional role of transglutaminase 2 (TGM2), we generated a TGM2 over-expression model. The antitumor efficacy in vivo was evaluated using the xenograft mouse model, and tumor growth, histology and immunohistochemistry were performed.
RESULTS
EPZ020411 inhibited CRC cell proliferation, migration, and invasion dose-dependently. IC50 values of EPZ020411 in HCT116 and CACO-2 cells at 48 hours were 126 μmol/L and 106 μmol/L. At 24 μmol/L, colony formation decreased by 32% and 50%, migration by ~62% in both lines, and invasion by 64% and 45%, respectively. Transcriptomic analysis revealed marked downregulation of TGM2, which was confirmed at both mRNA and protein levels. Mechanistically, EPZ020411 reduced phosphorylation of JNK and p38, indicating inactivation of the mitogen-activated protein kinases (MAPK) signaling pathway. Functional rescue experiments demonstrated that TGM2 overexpression partially reversed the inhibitory effects of EPZ020411. In vivo, EPZ020411 effectively suppressed tumor growth (45.1% inhibition at 10 mg/kg) without toxicity and reduced TGM2 expression in tumor tissues.
CONCLUSION
EPZ020411 inhibits CRC in vitro and in vivo via TGM2/MAPK, linking PRMT6-TGM2-MAPK, and suggesting PRMT6 as a potential therapeutic target.
Core Tip: In this study, we have found that EPZ020411 suppresses the growth and metastasis of colorectal cancer (CRC) cells. Mechanistically, EPZ020411 downregulates transglutaminase 2 (TGM2) and inhibits the JNK/p38 mitogen-activated protein kinases (MAPK) signaling pathway. Notably, TGM2 overexpression partially reverses these effects, highlighting its critical role as a downstream mediator. Overall, this study identified a novel protein arginine methyltransferase 6 (PRMT6)-TGM2-MAPK regulatory axis and provided a preliminary experimental basis for the potential of targeting PRMT6 in CRC, and new insights into the potential of targeting PRMT6 as a therapeutic strategy for CRC.
