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

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

doi:10.3389/fcell.2021.718707

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

Front Cell Dev Biol. 2021 Sep 1:9:718707. doi: 10.3389/fcell.2021.718707. eCollection 2021.

Authors

Meng Wang^{1

2}, Haoyu Liu¹, Xu Zhang¹, Wenbo Zhao³, Xiaoyan Lin⁴, Fei Zhang¹, Danyang Li^{1

5}, Chengpeng Xu¹, Fei Xie¹, Zhen Wu¹, Qibing Yang^{1

2}, Xiangzhi Li^{1

2}

Affiliations

¹ Shandong Provincial Key Laboratory of Animal Cell and Developmental Biology, School of Life Sciences, Advanced Medical Research Institute, Shandong University, Qingdao, China.
² Department of Cell and Neurobiology, School of Basic Medical Sciences, Shandong University, Jinan, China.
³ Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China.
⁴ Department of Pathology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China.
⁵ Department of Rehabilitation, Qilu Hospital of Shandong University, Jinan, China.

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.

Keywords: MOF; drug resistance; hepatocellular carcinoma; hypoxia; hypoxia inducible factor-1α; protein acetylation.