PIM1-HDAC2 axis modulates intestinal homeostasis through epigenetic modification

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外文摘要：The mucosal barrier is crucial for intestinal homeostasis,and goblet cells are essential for maintaining the mucosal barrier integrity.The proviral integration site for Moloney murine leukemia virus-1(PIM1)kinase regulates multiple cellular functions,but its role in intestinal homeostasis during colitis is unknown.Here,we demonstrate that PIM1 is prominently elevated in the colonic epithelia of both ulcerative colitis patients and murine models,in the presence of intestinal microbiota.Epithelial PIM1 leads to decreased goblet cells,thus impairing resistance to colitis and colitis-associated colorectal cancer(CAC)in mice.Mechanistically,PIM1 modulates goblet cell differentiation through the Wnt and Notch signaling pathways.Interestingly,PIM1 interacts with histone deacetylase 2(HDAC2)and down-regulates its level via phosphorylation,thereby altering the epigenetic profiles of Wnt signaling pathway genes.Collectively,these findings investigate the unknown function of the PIM1-HDAC2 axis in goblet cell differentiation and ulcerative colitis/CAC pathogenesis,which points to the potential for PIM1-targeted therapies of ulcerative colitis and CAC.

外文关键词：

PIM1HDAC2Goblet cellGut microbiotaIntestinal homeostasisEpigenetic modificationUlcerative colitisCAC

作者：

Jianming Yang、Yawen Xiao、Ningning Zhao、Geng Pei、Yan Sun、Xinyu Sun、Kaiyuan Yu、Chunhui Miao、Ran Liu、Junqiang Lv、Hongyu Chu、Lu Zhou、Bangmao Wang、Zhi Yao、Quan Wang

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作者单位：

Key Laboratory of Immune Microenvironment and Disease(Ministry of Education),Tianjin Institute of Immunology,State Key Laboratory of Experimental Hematology,the Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics,Department of Immunology,School of Basic Medical Sciences,Tianjin Institute of Urology,the Second Hospital of Tianjin Medical University,Tianjin Key Laboratory of Cellular and Molecular Immunology,Tianjin Medical University,Tianjin 300070,China

Department of Pathology,Tianjin Medical University Cancer Institute and Hospital

National Clinical Research Center of Cancer

Key Laboratory of Cancer Prevention and Therapy,Tianjin

Tianjin's Clinical Research Center of Cancer,Tianjin 30060,China

Department of Gastroenterology and Hepatology,Tianjin Medical University General Hospital,Tianjin Medical University,Tianjin 300070,China

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基金：

National Natural Science Foundation of China(NSFC)ProgramsNational Natural Science Foundation of China(NSFC)ProgramsNational Natural Science Foundation of China(NSFC)ProgramsTianjin Science and Technology Commissioner Project,ChinaTianjin Science and Technology Commissioner Project,China

项目编号：

32170186822006188217319922JCZDJC0049022JCQ NJC00540

出版年：

2024

DOI：

10.1016/j.apsb.2024.04.017

药学学报(英文版)

CSTPCD

ISSN：

年,卷(期)：2024.14(7)