Epigenetic Activation of the CMTM6-IGF2BP1-EP300 Positive Feedback Loop Drives Gemcitabine Resistance in Pancreatic Ductal Adenocarcinoma.

Publisher: WILEY-VCH Country of Publication: Germany NLM ID: 101664569 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2198-3844 (Electronic) Linking ISSN: 21983844 NLM ISO Abbreviation: Adv Sci (Weinh) Subsets: MEDLINE

Original Publication: Weinheim : WILEY-VCH, [2014]-

Deoxycytidine*/analogs & derivatives ; Deoxycytidine*/pharmacology ; Gemcitabine* ; Carcinoma, Pancreatic Ductal*/drug therapy ; Carcinoma, Pancreatic Ductal*/genetics ; Carcinoma, Pancreatic Ductal*/metabolism ; Drug Resistance, Neoplasm*/genetics ; Drug Resistance, Neoplasm*/drug effects ; Pancreatic Neoplasms*/drug therapy ; Pancreatic Neoplasms*/genetics ; Pancreatic Neoplasms*/metabolism ; RNA-Binding Proteins*/genetics ; RNA-Binding Proteins*/metabolism ; Epigenesis, Genetic*/genetics ; Epigenesis, Genetic*/drug effects ; E1A-Associated p300 Protein*/metabolism ; E1A-Associated p300 Protein*/genetics; Humans ; Mice ; Animals ; Feedback, Physiological/drug effects ; Cell Line, Tumor ; Antimetabolites, Antineoplastic/pharmacology ; Antimetabolites, Antineoplastic/therapeutic use ; Disease Models, Animal

Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant tumor with a dismal prognosis. Gemcitabine-based chemotherapy has emerged as a first-line treatment for PDAC. However, the development of gemcitabine resistance often results in therapeutic failure. In order to uncover the underlying mechanisms of gemcitabine resistance, gemcitabine-resistant PDAC cell lines and patient-derived xenograft (PDX) models are established and subjected to RNA sequencing. It is found that CMTM6 is closely related to gemcitabine resistance in PDAC. Multi-omics analysis revealed that EP300-mediated H3K27ac modification is involved in the transcriptional activation of CMTM6, which maintains IGF2BP1 expression by preventing its ubiquitination. The m ⁶ A reader IGF2BP1 stabilizes the EP300 and MYC mRNAs by recognizing m ⁶ A modifications, forming a positive feedback loop that enhances tumor stemness and ultimately contributes to PDAC resistance. The combined application of the EP300 inhibitor inobrodib and gemcitabine exerts a synergistic effect on PDAC. Overall, these findings reveal that the EP300-CMTM6-IGF2BP1 positive feedback loop facilitates gemcitabine resistance via epigenetic reprogramming and the combined use of inobrodib and gemcitabine represents a promising strategy for overcoming chemoresistance in PDAC, warranting further investigation in clinical trials.
(© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

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82072644 National Natural Science Foundation of China; 82203473 National Natural Science Foundation of China; 82203105 National Natural Science Foundation of China; 82103401 National Natural Science Foundation of China; 202201010927 Guangzhou Science and Technology Program Project; 2022A1515111221 Basic and Applied Basic Research Foundation of Guangdong Province; 2021A1515111104 Basic and Applied Basic Research Foundation of Guangdong Province; 2021A1515010123 Basic and Applied Basic Research Foundation of Guangdong Province; 2023A1515110874 Basic and Applied Basic Research Foundation of Guangdong Province; 2024A1515010487 Basic and Applied Basic Research Foundation of Guangdong Province

Keywords: CMTM6; N6‐methyladenosine; chemoresistance; epigenetic modification; pancreatic ductal adenocarcinoma

0W860991D6 (Deoxycytidine)
0 (Gemcitabine)
0 (RNA-Binding Proteins)
EC 2.3.1.48 (E1A-Associated p300 Protein)
0 (IGF2BP1 protein, human)
EC 2.3.1.48 (EP300 protein, human)
0 (Antimetabolites, Antineoplastic)

Date Created: 20241103 Date Completed: 20241218 Latest Revision: 20241218

20241218

10.1002/advs.202406714

39488785