HOXB9 blocks cell cycle progression to inhibit pancreatic cancer cell proliferation through the DNMT1/RBL2/c-Myc axis

Yang Yao; Chao Liu; Bojun Wang; Xin Guan; Lin Fang; Fei Zhan; Haoxiu Sun; Hengzhen Li; Changjie Lou; Feihu Yan; Xiaolin Lu; Luying Cui; Yuanyu Liao; Shuling Han; Yuanfei Yao; Yanqiao Zhang

doi:10.1016/j.canlet.2022.215595

HOXB9 blocks cell cycle progression to inhibit pancreatic cancer cell proliferation through the DNMT1/RBL2/c-Myc axis

Cancer Lett. 2022 May 1:533:215595. doi: 10.1016/j.canlet.2022.215595. Epub 2022 Feb 16.

Authors

Yang Yao¹, Chao Liu¹, Bojun Wang², Xin Guan², Lin Fang², Fei Zhan², Haoxiu Sun³, Hengzhen Li², Changjie Lou², Feihu Yan², Xiaolin Lu², Luying Cui², Yuanyu Liao², Shuling Han², Yuanfei Yao⁴, Yanqiao Zhang⁵

Affiliations

¹ Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China; Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin, China; Heilongjiang Province Key Laboratory of Tumor Immunology, China.
² Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China; Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin, China.
³ School of Life Science and Technology, Harbin Institute of Technology, Harbin, China.
⁴ Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China; Heilongjiang Province Key Laboratory of Tumor Immunology, China; Heilongjiang Province Key Laboratory of Molecular Oncology, China. Electronic address: yaoyuanfei@hrbmu.edu.cn.
⁵ Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China; Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin, China; Heilongjiang Province Key Laboratory of Tumor Immunology, China. Electronic address: yanqiaozhang@ems.hrbmu.edu.cn.

PMID: 35182659
DOI: 10.1016/j.canlet.2022.215595

Abstract

Homeobox B9 (HOXB9) is involved in the occurrence and development of malignant tumors. However, the functions and underlying molecular mechanisms of HOXB9 in pancreatic cancer have yet to be identified. In this study, we find that both HOXB9 mRNA and protein levels are down-regulated in pancreatic cancer tissues and cell lines. Kaplan-Meier survival plots of 150 pancreatic cancer cases show that higher expression of HOXB9 in pancreatic cancer patients is associated with higher survival rates. We also find that over-expression of HOXB9 inhibits pancreatic cancer cell proliferation both in cell lines and the nude mouse xenograft as well as PDX models. Applying cell cycle PCR array analysis, Flow CytoMetry, ChIP-qPCR, and luciferase experiments, we observe that HOXB9 blocks cell cycle progression in the G0/G1 phase via up-regulating RBL2 and inhibiting c-Myc, and we further find that DNMT1 inhibits the expression of HOXB9 in pancreatic cancer by promoting the methylation of its promoter. Our findings highlight a novel mechanism of the DNMT1/HOXB9/RBL2/c-Myc pathway in regulating the cell cycle and proliferation of pancreatic cancer cells and provide a research basis for the prognosis and therapeutic application of HOXB9 in pancreatic cancer.

Keywords: Cell cycle; DNMT1; HOXB9; Pancreatic cancer; RBL2.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Cycle / genetics
Cell Division
Cell Line, Tumor
Cell Proliferation
Gene Expression Regulation, Neoplastic*
Homeodomain Proteins / genetics
Homeodomain Proteins / metabolism
Humans
Mice
Pancreatic Neoplasms* / genetics
Retinoblastoma-Like Protein p130 / genetics

Substances

HOXB9 protein, human
Homeodomain Proteins
RBL2 protein, human
Retinoblastoma-Like Protein p130