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

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.

SUBMITTER: Wang M

PROVIDER: S-EPMC8440882 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundHypoxia is a hallmark of cancer, and is closely intertwined with tumor immune evasion. Circular RNAs (circRNAs) have been implicated in tumor response to immune checkpoint blockades. However, hypoxia-associated circRNAs that orchestrate the association between hypoxia and response to immunotherapy remain poorly understood. Here, we aimed to determine the roles of hypoxia-associated circRNAs in immune escape of hepatocellular carcinoma (HCC) cells.MethodsDifferentially expressed hypoxia-associated circRNAs were determined using high-throughput sequencing technology. HCC patients treated with PD-1 blockade were enrolled to assess the clinical significance of circPRDM4. RT-qPCR, western blotting, flow cytometry, T cell-mediated tumor cell killing assay, and enzyme linked immunosorbent assay were used to investigate the roles of circPRDM4 in immune escape of HCC cells in vitro. Patient-derived xenograft mouse models and adoptive human tumor infiltrating lymphocyte-CD8+ T cell transfer were adopted to evaluate the effects of circPRDM4 in vivo. RNA pull-down, mass spectrometry, RNA immunoprecipitation, chromatin immunoprecipitation, chromatin isolation by RNA purification, dual-luciferase reporter assays, dot blotting, DNA in situ hybridization, and immunoprecipitation were utilized to examine the interaction between circPRDM4, HIF-1α, and CD274 promoter.ResultsWe identified circPRDM4 as a hypoxia-associated circRNA in HCC. circPRDM4 was upregulated in responders to PD-1 blockade and associated with therapeutic efficacy. In vitro and in vivo experiments showed that circPRDM4 induced PD-L1 expression and promoted CD8+ T cell-mediated immune escape under hypoxic conditions. Mechanistically, circPRDM4 acted as a scaffold to recruit HIF-1α onto CD274 promoter, and cemented their interaction, ultimately promoting the HIF-1α-mediated transactivation of PD-L1.ConclusionsThese findings illustrated that circPRDM4 promoted immune escape of HCC cells by facilitating the recruitment of HIF-1α onto the promoter of CD274 under hypoxia, thereby inhibiting CD8+ T cell infiltration in the tumor microenvironment. This work may provide a novel prognostic biomarker and therapeutic candidate for HCC immunotherapy.

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

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