SMYD2 Imparts Gemcitabine Resistance to Pancreatic Adenocarcinoma Cells by Upregulating EVI2A.

Publisher: Springer Country of Publication: Switzerland NLM ID: 9423533 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1559-0305 (Electronic) Linking ISSN: 10736085 NLM ISO Abbreviation: Mol Biotechnol Subsets: MEDLINE

Publication: [Cham] : Springer
Original Publication: Totowa, NJ : Humana Press, c1994-

Gemcitabine* ; Deoxycytidine*/analogs & derivatives ; Deoxycytidine*/pharmacology ; Drug Resistance, Neoplasm*/genetics ; Pancreatic Neoplasms*/genetics ; Pancreatic Neoplasms*/metabolism ; Pancreatic Neoplasms*/pathology ; Pancreatic Neoplasms*/drug therapy ; Histone-Lysine N-Methyltransferase*/genetics ; Histone-Lysine N-Methyltransferase*/metabolism; Humans ; Cell Line, Tumor ; Gene Expression Regulation, Neoplastic ; Adenocarcinoma/genetics ; Adenocarcinoma/drug therapy ; Adenocarcinoma/pathology ; Adenocarcinoma/metabolism ; Up-Regulation ; Cell Proliferation/drug effects ; Apoptosis/drug effects ; Macrophages/metabolism ; Macrophages/immunology ; Antimetabolites, Antineoplastic/pharmacology ; Cell Movement

Although gemcitabine (GEM) is the first‑line drug for advanced pancreatic adenocarcinoma (PAAD), the development of GEM resistance severely limits the effectiveness of this chemotherapy. This study investigated the mechanisms of ecotropic viral integration site 2 A (EVI2A) for resistance to GEM and immune evasion in PAAD. GEM resistance-related biomarkers were predicted using GEO datasets, and GEM-resistant PAAD cells were generated. EVI2A was found expressed highly in GEM-resistant PAAD cells. Gain-of-function analyses revealed that EVI2A encouraged the proliferation and motility of GEM-resistant cells and prevented apoptosis. In addition, EVI2A reduced T cell effector activation. SMYD2 was overexpressed in GEM-resistant cells, and SMYD2 enhanced H3K36me2 modification of EVI2A, thereby promoting EVI2A expression. SMYD2 reduced the sensitivity of GEM-resistant cells, which was reversed by EVI2A knockdown. SMYD2 increased the amount of M2 macrophages (co-cultured with PAAD cells) and decreased T cell effector activation (co-cultured with macrophage supernatant), and the number of M2 macrophages was decreased and T cell effectors were activated following EVI2A knockdown. Our findings indicate that EVI2A, manipulated by the SMYD2-H3K36me2 epigenetic axis, promoted GEM resistance and M2 macrophage-mediated immune evasion in PAAD. Therefore, EVI2A might represent a therapeutic target for overcoming GEM resistance and immunosuppressive environment in PAAD.
(© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

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KJ2020A0614 Key Natural Science Foundation of Anhui Provincial Department of Education; GXXT-2020-023 Anhui Provincial Department of Education University Collaborative Research and Innovation Natural Science Fund

Keywords: EVI2A; Gemcitabine; Immune evasion; Pancreatic adenocarcinoma; SMYD2

0 (Gemcitabine)
0W860991D6 (Deoxycytidine)
EC 2.1.1.43 (Histone-Lysine N-Methyltransferase)
EC 2.1.1.43 (SMYD2 protein, human)
0 (Antimetabolites, Antineoplastic)

Date Created: 20231009 Date Completed: 20241010 Latest Revision: 20241015

20241016

10.1007/s12033-023-00908-7

37812330