ZNF281 inhibits mitochondrial biogenesis to facilitate metastasis of hepatocellular carcinoma

Author:

Zhao QingfangORCID,Zhang ChenguangORCID,Zhang Xialu,Wang Shanshan,Guo Ting,Yin Yuzhe,Zhang Hui,Li Zhuo,Si Yang,Lu Yabin,Cheng ShanORCID,Ding WeiORCID

Abstract

AbstractZinc finger protein 281 (ZNF281) has been shown to promote tumor progression. However, the underlying mechanism remains to be further elucidated. In this study, ZNF281 knockdown increased the expression of mitochondrial transcription factor A (TFAM) in hepatocellular carcinoma (HCC) cells, accompanied with increment of mitochondrial content, oxygen consumption rate (OCR) and levels of TCA cycle intermetabolites. Mechanistic investigation revealed that ZNF281 suppressed the transcription of TFAM, nuclear respiratory factor 1 (NRF1) and peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α). Furthermore, ZNF281 interacted with NRF1 and PGC-1α, and was recruited onto the promoter regions of TFAM, TFB1M and TFB2M repressing their expression. Knockdown of TFAM reversed ZNF281 depletion induced up-regulation of mitochondrial biogenesis and function, as well as impaired epithelial mesenchymal transition, invasion and metastasis of HCC cells. Our research uncovered a novel suppressive function of ZNF281 on mitochondrial biogenesis through inhibition of the NRF1/PGC-1α-TFAM axis, which may hold therapeutic potentials for HCC.

Funder

National Natural Science Foundation of China

Natural Science Foundation of Beijing Municipality

Publisher

Springer Science and Business Media LLC

Subject

Cancer Research,Cell Biology,Cellular and Molecular Neuroscience,Immunology

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