ZHX2 inhibits SREBP1c-mediated de novo lipogenesis in hepatocellular carcinoma via miR-24-3p.

Abstract

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide. Lipogenesis has been considered as a critical player in HCC initiation and progression. However, the underlying mechanism is still not fully understood. Here, we identified zinc fingers and homeoboxes 2 (ZHX2), an HCC-associated tumor suppressor, as an important repressor of de novo lipogenesis. Ectopic expression of ZHX2 significantly inhibited de novo lipogenesis in HCC cells and decreased expression of FASN, ACL, ACC1, and SCD1. In accordance with this, ZHX2 was negatively associated with SREBP1c, the master regulator of de novo lipogenesis, in HCC cell lines and human specimens. Results from silencing and overexpression demonstrated that ZHX2 inhibited de novo lipogenesis and consequent HCC progression via repression of SREBP1c. Furthermore, treatment with the SREBP1c inhibitor fatostatin dampened the spontaneous formation of tumors in liver-specific Zhx2 knockout mice. Mechanistically, ZHX2 increased expression of miR-24-3p transcriptionally, which targeted SREBP1c and led to its degradation. In conclusion, our data suggest a novel mechanism through which ZHX2 suppresses HCC progression, which may provide a new strategy for the treatment of HCC. © 2020 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

• Authors: Xiangguo Yu, Qinghai Lin, Zhuanchang Wu, Yankun Zhang, Tixiao Wang, Songbai Zhao, Xiaojia Song, Chaojia Chen, Zehua Wang, Leiqi Xu, Chunyang Li, Lifen Gao, Xiaohong Liang, Xuetian Yue, Chunhong Ma
• Journal: The Journal of pathology (J Pathol) Vol. 252 Issue 4 Pg. 358-370 (12 2020) ISSN: 1096-9896 [Electronic] England
• PMID: 32770671 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Chemical References

• Fatty Acids, Nonesterified
• Homeodomain Proteins
• MIRN24 microRNA, human
• MicroRNAs
• Pyridines
• Sterol Regulatory Element Binding Protein 1
• Thiazoles
• Transcription Factors
• Triglycerides
• ZHX2 protein, human
• fatostatin

Topics

• Adult
• Aged
• Animals
• Carcinogenesis (genetics)
• Carcinoma, Hepatocellular (genetics, metabolism, pathology)
• Cell Line, Tumor
• Cell Proliferation (genetics)
• Disease Models, Animal
• Fatty Acids, Nonesterified (metabolism)
• Female
• Gene Expression Regulation, Neoplastic
• Hep G2 Cells
• Hepatocytes (drug effects, metabolism, pathology)
• Homeodomain Proteins (genetics, metabolism)
• Humans
• Lipogenesis (genetics)
• Liver Neoplasms (genetics, metabolism, pathology)
• Male
• Mice
• Mice, Knockout
• MicroRNAs (genetics, metabolism)
• Middle Aged
• Pyridines (pharmacology)
• Sterol Regulatory Element Binding Protein 1 (antagonists & inhibitors, genetics, metabolism)
• Thiazoles (pharmacology)
• Transcription Factors (genetics, metabolism)
• Triglycerides (metabolism)