GRIM-19 inhibits proliferation and induces apoptosis in a p53-dependent manner in colorectal cancer cells through the SIRT7/PCAF/MDM2 axis

Ding Wang; Xiaodong Wei; Xuyang Chen; Qian Wang; Jinghua Zhang; Dhan V Kalvakolanu; Baofeng Guo; Ling Zhang

doi:10.1016/j.yexcr.2021.112799

GRIM-19 inhibits proliferation and induces apoptosis in a p53-dependent manner in colorectal cancer cells through the SIRT7/PCAF/MDM2 axis

Exp Cell Res. 2021 Oct 1;407(1):112799. doi: 10.1016/j.yexcr.2021.112799. Epub 2021 Aug 28.

Authors

Ding Wang¹, Xiaodong Wei¹, Xuyang Chen¹, Qian Wang¹, Jinghua Zhang¹, Dhan V Kalvakolanu², Baofeng Guo³, Ling Zhang⁴

Affiliations

¹ Key Laboratory of Pathobiology, Ministry of Education, And Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun, PR China.
² Greenebaum NCI Comprehensive Cancer Center, Department of Microbiology and Immunology University of Maryland School Medicine, Baltimore, MD, USA.
³ Department of Plastic Surgery, China-Japan Union Hospital of Jilin University, Changchun, PR China. Electronic address: gbf@jlu.edu.cn.
⁴ Key Laboratory of Pathobiology, Ministry of Education, And Department of Pathophysiology, College of Basic Medical Sciences, Jilin University, Changchun, PR China. Electronic address: zhangling3@jlu.edu.cn.

PMID: 34461110
DOI: 10.1016/j.yexcr.2021.112799

Abstract

Colorectal cancer (CRC) is the leading deadly cancer worldwide. Gene associated with retinoid-IFN-induced mortality-19 (GRIM-19), a novel tumor suppressor, has been reported to be expressed at low levels in human CRC. However, the role of GRIM-19 in CRC progression and the corresponding detailed mechanisms are unclear. The results of this study indicated that GRIM-19 expression is related to CRC progression. Overexpression of GRIM-19 was found to inhibit CRC cell proliferation and induce apoptosis in vitro and in vivo. Our results demonstrated that GRIM-19 suppresses CRC through posttranslational regulation of p53, in which SIRT7 is activated by GRIM-19 and triggers PCAF-mediated MDM2 ubiquitination, eventually stabilizing the p53 protein. We also observed that GRIM-19 enhances the effect of oxaliplatin against CRC. In conclusion, GRIM-19 plays an important role in CRC development and is a potential biomarker and therapeutic target for clinical treatment of CRC.

Keywords: CRC; GRIM-19; MDM2; SIRT7; p53.

Publication types

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

MeSH terms

Apoptosis / physiology*
Apoptosis Regulatory Proteins / metabolism*
Cell Line, Tumor
Cell Proliferation / physiology*
Colorectal Neoplasms / metabolism*
Colorectal Neoplasms / pathology
Gene Expression Regulation, Neoplastic / physiology
Genes, Tumor Suppressor / physiology
Humans
NADH, NADPH Oxidoreductases / metabolism*
Proto-Oncogene Proteins c-mdm2 / metabolism
Sirtuins / metabolism
Tumor Suppressor Protein p53 / metabolism*
Ubiquitination / physiology

Substances

Apoptosis Regulatory Proteins
SIRT7 protein, human
TP53 protein, human
Tumor Suppressor Protein p53
NADH, NADPH Oxidoreductases
NDUFA13 protein, human
MDM2 protein, human
Proto-Oncogene Proteins c-mdm2
Sirtuins