USP22 promotes hypoxia-induced hepatocellular carcinoma stemness by a HIF1α/USP22 positive feedback loop upon TP53 inactivation

Ling, Sunbin; Shan, Qiaonan; Zhan, Qifan; Ye, Qianwei; Liu, Peng; Xu, Shengjun; He, Xin; Ma, Jian; Xiang, Jiajia; Jiang, Guangjiang; Wang, Xue; Feng, Zijie; Wu, Yuan; Feng, Tingting; Liu, Xu; Chen, Kangchen; Zhang, Xuanyu; Wei, Ran; Zhang, Chenzhi; Cen, Beini; Xie, Haiyang; Song, Penghong; Liu, Jimin; Zheng, Shusen; Xu, Xiao

doi:10.1136/gutjnl-2019-319616

Cited by 144 publications

(125 citation statements)

References 42 publications

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“…The formation of the feedback loop was essential in cancer progression 19 , 54 . Meanwhile, the involvement of Myc has been indicated in certain positive or negative feedback loops.…”

Section: Discussionmentioning

confidence: 99%

A reciprocal feedback of Myc and lncRNA MTSS1-AS contributes to extracellular acidity-promoted metastasis of pancreatic cancer

Wang

et al. 2020

Theranostics

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Rationale: Previous studies have reported on the role of extracellular acidity in the metastasis of numerous cancers. However, the involvement of long noncoding RNA (lncRNA) in the extracellular acidity-induced cancer metastasis of pancreatic cancer (PC) remains unclear. Methods: Different expression levels of lncRNAs in PC cells under normal and acidic conditions were compared by RNA sequencing (RNA-seq). The effects of antisense lncRNA of metastasis suppressor 1 (MTSS1-AS) on acidic PC cells were assessed by gain- and loss-of-function experiments. Fluorescence in situ hybridization, RNA immunoprecipitation, RNA pull-down, Western blot, luciferase reporter, and Chromatin immunoprecipitation assays were employed to determine the regulatory mechanisms of MTSS1-AS in the acidity-induced metastasis of PC cells. The expression of MTSS1-AS and associated pathways were compared in PC samples and peritumoral normal tissues. Results: RNA-seq demonstrated that MTSS1-AS was significantly downregulated in pancreatic cells cultured with the acidic medium. The overexpression of MTSS1-AS remarkably inhibited the acidity-promoted metastasis of PC cells by upregulating the expression of its sense gene metastasis suppressor 1 (MTSS1). Mechanistically, MTSS1-AS scaffolded the interaction between E3 ubiquitin-protein ligase STIP1 homology and U-box containing protein 1 (STUB1) and transcription regulator myeloid zinc finger 1 (MZF1), leading to ubiquitination-mediated degradation of MZF1. Further, MZF1 inhibited the expression of MTSS1 by binding to the MTSS1 promoter. Thus, the acidity-reduced MTSS1-AS facilitated the stability of MZF1 and its inhibitory effect on MTSS1 transcription, thereby promoting the metastasis of PC cells under acidic conditions. Moreover, MTSS1-AS was transcriptionally repressed by the binding of MYC proto-oncogene (Myc) with initiator (Inr) elements of the MTSS1-AS promoter. Meanwhile, MTSS1-AS mutually repressed the expression of Myc by impairing the MZF1-mediated transcription activation of Myc, thereby forming a negative feedback loop between MTSS1-AS and Myc in acidic PC cells. In accordance with the experimental results, MTSS1-AS and MTSS1 were downregulated in PC and correlated with poor overall survival. Conclusions: The results implicated that a reciprocal feedback loop between Myc and MTSS1-AS contributed to the extracellular acidity-promoted metastasis of PC, and indicated that MTSS1-AS was a valuable biomarker and therapeutic target for PC.

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“…The formation of the feedback loop was essential in cancer progression 19 , 54 . Meanwhile, the involvement of Myc has been indicated in certain positive or negative feedback loops.…”

Section: Discussionmentioning

confidence: 99%

A reciprocal feedback of Myc and lncRNA MTSS1-AS contributes to extracellular acidity-promoted metastasis of pancreatic cancer

Wang

et al. 2020

Theranostics

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“…Due to uncontrolled growth of HCC leading to intratumor hypoxia, HCC cells are developed with the capacity of more stemness, chemoresistance, and invasive 9,10 . The interactions between hypoxic microenvironment and HCC cells are considered as a key factor causing sorafenib chemotherapy failure 11 .…”

Section: Introductionmentioning

confidence: 99%

Hypoxia induces sorafenib resistance mediated by autophagy via activating FOXO3a in hepatocellular carcinoma

et al. 2020

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Sorafenib, a multikinase inhibitor, is considered as the only approved drug to cure the advanced hepatocellular carcinoma (HCC); however, the acquired chemoresistance caused by intratumoral hypoxia through sorafenib long term therapy induces sorafenib inefficacy. We demonstrated here that hypoxia significantly attenuated sensitivity of HCC cells to sorafenib treatment and reduced its proliferation. Autophagy was observed in sorafenib-treated HCC cells in hypoxia, and inhibition of autophagy by 3-MA eliminated hypoxia-induced sorafenib resistance. Further study revealed hypoxia-activated FOXO3a, an important cellular stress transcriptional factor, via inducing its dephosphorylation and nuclear location; and FOXO3a-dependent transcriptive activation of beclin-1 was responsible for hypoxia-induced autophagy in HCC cells. Knockout of FOXO3a inhibited the autophagy induced by sorafenib itself in normoxia and significantly enhanced the cytotoxicity of sorafenib in HCC cells; and it also inhibited the hypoxia-induced autophagy and achieved the same effect in sorafenib sensitivity-enhancement in HCC cells as it in normoxia. Finally, knockout of intratumoral FOXO3a significantly enhanced curative efficacy of sorafenib via inhibition of autophagy in xenograft tumors in nude mice. Collectively, our study suggests that FOXO3a plays a key role in regulating hypoxia-induced autophagy in sorafenib-treated HCC, and FOXO3-targeted therapy may serve as a promising approach to improve clinical prognosis of patients suffering from HCC.

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“…Hypoxia leads to HIF-1a stabilization and rapid protein accumulation and increased transcriptional activity (5). Through transcription of several hundred of target genes, HIF-1a is profoundly implicated in many malignant phenotypes, such as angiogenesis, metabolic reprogramming, stemness maintenance, cell survival and proliferation, tumor motility and invasion, immune evasion, and resistance to chemoresistance (6)(7)(8)(9). Recent preclinical studies showed that the combination of cytotoxic chemotherapy with drugs that targeting hypoxia-inducible factors may improve the clinical outcome for TNBC patients (10)(11)(12).…”

Section: Introductionmentioning

confidence: 99%

Long Noncoding RNA MIR210HG Promotes the Warburg Effect and Tumor Growth by Enhancing HIF-1α Translation in Triple-Negative Breast Cancer

Wei

et al. 2020

Front. Oncol.

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BackgroundHypoxia is an important environmental factor and has been correlated with tumor progression, treatment resistance and poor prognosis in many solid tumors, including triple-negative breast cancer (TNBC). Emerging evidence suggests that long noncoding RNA (lncRNA) functions as a critical regulator in tumor biology. However, little is known about the link between hypoxia and lncRNAs in TNBC.MethodsTNBC molecular profiles from The Cancer Genome Atlas (TCGA) were leveraged to identify hypoxia-related molecular alterations. Loss-of-function studies were performed to determine the regulatory role of MIR210HG in tumor glycolysis. The potential functions and mechanisms of hypoxia-MIR210HG axis were explored using qPCR, Western blotting, luciferase reporter assay, and polysome profiling.ResultsWe found that MIR210HG is a hypoxia-induced lncRNA in TNBC. Loss-of-function studies revealed that MIR210HG promoted the Warburg effect as demonstrated by glucose uptake, lactate production and expression of glycolytic components. Mechanistically, MIR210HG potentiated the metabolic transcription factor hypoxia-inducible factor 1α (HIF-1α) translation via directly binding to the 5’-UTR of HIF-1α mRNA, leading to increased HIF-1a protein level, thereby upregulating expression of glycolytic enzymes. MIR210HG knockdown in TNBC cells reduced their glycolytic metabolism and abolished their tumorigenic potential, indicating the glycolysis-dependent oncogenic activity of MIR210HG in TNBC. Moreover, MIR210HG was highly expressed in breast cancer and predicted poor clinical outcome.ConclusionOur results decipher a positive feedback loop between hypoxia and MIR210HG that drive the Warburg effect and suggest that MIR210HG may be a good prognostic marker and therapeutic target for TNBC patients.

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USP22 promotes hypoxia-induced hepatocellular carcinoma stemness by a HIF1α/USP22 positive feedback loop upon TP53 inactivation

Cited by 144 publications

References 42 publications

A reciprocal feedback of Myc and lncRNA MTSS1-AS contributes to extracellular acidity-promoted metastasis of pancreatic cancer

A reciprocal feedback of Myc and lncRNA MTSS1-AS contributes to extracellular acidity-promoted metastasis of pancreatic cancer

Hypoxia induces sorafenib resistance mediated by autophagy via activating FOXO3a in hepatocellular carcinoma

Long Noncoding RNA MIR210HG Promotes the Warburg Effect and Tumor Growth by Enhancing HIF-1α Translation in Triple-Negative Breast Cancer

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