Lack of MOF Decreases Susceptibility to Hypoxia and Promotes Multidrug Resistance in Hepatocellular Carcinoma via HIF-1α

Meng Wang,Fei Xie,Danyang Li,Haoyu Liu,Xiangzhi Li,Chengpeng Xu,Fei Zhang,Xiaoyan Lin,Xu Zhang,Wenbo Zhao,Qibing Yang,Zhen Wu

doi:10.3389/fcell.2021.718707

Abstract

Hypoxia-inducible factor-1α (HIF-1α) promotes oncogenesis in hepatocellular carcinoma and is functionally linked to cell proliferation, chemoresistance, metastasis and angiogenesis. It has been confirmed that the low expression level of Males absent on the first (MOF) in hepatocellular carcinoma leads to poor prognosis of patients. However, potential regulatory mechanisms of MOF in response to hypoxia remain elusive. Our results demonstrate that MOF expression is negatively associated with HIF-1α expression in hepatocellular carcinoma tissues and in response to chloride-mimicked hypoxia in hepatocellular carcinoma cell lines. MOF regulates HIF-1α mRNA expression and also directly binds to HIF-1α to mediate HIF-1α N-terminal lysine acetylation, ubiquitination and degradation, with downstream effects on MDR1 levels. Functional inactivation of MOF enhances HIF-1α stability and causes cell tolerance to hypoxia that is insensitive to histone deacetylase inhibitor treatment. Dysfunction of MOF in hepatocellular carcinoma cells also results in chemoresistance to trichostatin A, sorafenib and 5-fluorouracil via HIF-1α. Our results suggest that MOF regulates hypoxia tolerance and drug resistance in hepatocellular carcinoma cells by modulating both HIF-1α mRNA expression and N-terminal acetylation of HIF-1α, providing molecular insight into MOF-dependent oncogenic function of hepatocellular carcinoma cells.

Highlights

Liver cancer is the fourth most diagnosed cancer type and the third leading cause of cancer-related death in China (Feng et al, 2019)
Males absent on the first (MOF) inhibitor MG149, eukaryote protein synthesis inhibitor CHX, proteasome inhibitor MG132, histone deacetylases (HDACs) inhibitor trichostatin A (TSA), and Hypoxia-inducible factor-1α (HIF-1α) inhibitor LW6 were purchased from MedChemExpress (MCE, Princeton, NJ, United States). 5-FU, CoCl2, MTT and Tween 20 were purchased from Aladdin (Shanghai, China)
There is no research evaluating the relationship between MOF expression and HIF-1α expression in liver cancer

Summary

Introduction

Liver cancer is the fourth most diagnosed cancer type and the third leading cause of cancer-related death in China (Feng et al, 2019). In HCC, HIF-1α functions as an oncogene, mediating cell proliferation, tumor chemoresistance, metastasis, glycolysis and angiogenesis (Wu et al, 2016; Abu-Remaileh et al, 2018; Qin et al, 2018; Wen et al, 2019). Deacetylation at N-terminal lysine residues (K10, K11, K12, K19, and K21) (Geng et al, 2011; Zhang et al, 2017) and acetylation at C-terminal lysine residues (K532, K674, and K709) (Xenaki et al, 2008; Lim et al, 2010; Geng et al, 2012) have been shown to enhance the protein stability of HIF-1α, promoting tumor cell tolerance to hypoxic conditions (Geng et al, 2011). Treatment of cells with HDAC inhibitors, such as trichostatin A (TSA), leads to HIF-1α degradation (Schoepflin et al, 2016)

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Results

Conclusion