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Hypoxia-induced proteasomal degradation of DBC1 by SIAH2 in breast cancer progression.

ABSTRACT: DBC1 has been characterized as a key regulator of physiological and pathophysiological activities, such as DNA damage, senescence, and tumorigenesis. However, the mechanism by which the functional stability of DBC1 is regulated has yet to be elucidated. Here, we report that the ubiquitination-mediated degradation of DBC1 is regulated by the E3 ubiquitin ligase SIAH2 and deubiquitinase OTUD5 under hypoxic stress. Mechanistically, hypoxia promoted DBC1 to interact with SIAH2 but not OTUD5, resulting in the ubiquitination and subsequent degradation of DBC1 through the ubiquitin-proteasome pathway. SIAH2 knockout inhibited tumor cell proliferation and migration, which could be rescued by double knockout of SIAH2/CCAR2. Human tissue microarray analysis further revealed that the SIAH2/DBC1 axis was responsible for tumor progression under hypoxic stress. These findings define a key role of the hypoxia-mediated SIAH2-DBC1 pathway in the progression of human breast cancer and provide novel insights into the metastatic mechanism of breast cancer.

SUBMITTER: Liu Q

PROVIDER: S-EPMC9377797 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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Hypoxia-induced proteasomal degradation of DBC1 by SIAH2 in breast cancer progression.

Liu Qiangqiang Q Luo Qian Q Feng Jianyu J Zhao Yanping Y Ma Biao B Cheng Hongcheng H Zhao Tian T Lei Hong H Mu Chenglong C Chen Linbo L Meng Yuanyuan Y Zhang Jiaojiao J Long Yijia Y Su Jingyi J Chen Guo G Li Yanjun Y Hu Gang G Liao Xudong X Chen Quan Q Zhu Yushan Y

eLife 20220801

DBC1 has been characterized as a key regulator of physiological and pathophysiological activities, such as DNA damage, senescence, and tumorigenesis. However, the mechanism by which the functional stability of DBC1 is regulated has yet to be elucidated. Here, we report that the ubiquitination-mediated degradation of DBC1 is regulated by the E3 ubiquitin ligase SIAH2 and deubiquitinase OTUD5 under hypoxic stress. Mechanistically, hypoxia promoted DBC1 to interact with SIAH2 but not OTUD5, resulti ...[more]

PMID: 35913115

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Project description:AimsHypoxia induces vascular inflammation by a mechanism not fully understood. Emerging evidence implicates O-GlcNAc transferase (OGT) in inflammation. This study explored the role of OGT in hypoxia-induced vascular endothelial inflammatory response.Methods and resultsHypoxia was either induced (1% O2 chamber) or mimicked by exposure to hypoxia-mimetic agents in cultured endothelial cells. Hypoxia increased hypoxia-inducible factor (HIF-1α) and inflammatory response (gene and protein expression of interleukin (IL)-6, IL-8, monocyte chemoattractant protein-1, and E-selectin) but, surprisingly, reduced OGT protein (not mRNA) levels. Hypoxia-mimetic CoCl2 failed to reduce OGT when proteasome inhibitors were present, suggesting proteasome involvement. Indeed, CoCl2 enhanced 26S proteasome functionality evidenced by diminished reporter (Ub(G76V)-GFP) proteins in proteasome reporter cells, likely due to increased chymotrypsin-like activities. Mechanistically, β-TrCP1 mediated OGT degradation, since siRNA ablation of this E3 ubiquitin ligase stabilized OGT. Administration of the oxidative stress inhibitors reversed both proteasome activation and OGT degradation. Furthermore, up-regulation of OGT by stabilization, overexpression, or activation mitigated CoCl2-elicited inflammatory response. These observations were recapitulated in a mouse (C57BL/6J) model mimicking hypoxia, in which lung tissues presented higher levels of HIF-1α, proteasome activity, and inflammatory response, but lower levels of OGT (n = 5/group, hypoxia vs. normoxia, P < 0.05). However, administration of an activator of OGT (glucosamine: 1 mg/g/day, vehicle: saline, ip, 5 days) abolished the up-regulation of proteasome activity and inflammatory response (n = 5/group, the treated vs. untreated hypoxia groups, P < 0.05).Conclusions26S proteasome-mediated OGT reduction contributed to hypoxia-induced vascular endothelial inflammatory response. Modulation of OGT may represent a new approach to treat diseases characterized by hypoxic inflammation.

Project description:Two pathways are responsible for the majority of regulated protein catabolism in eukaryotic cells: the ubiquitin-proteasome system (UPS) and lysosomal self-degradation through autophagy. Both processes are necessary for cellular homeostasis by ensuring continuous turnover and quality control of most intracellular proteins. Recent studies established that both UPS and autophagy are capable of selectively eliminating ubiquitinated proteins and that autophagy may partially compensate for the lack of proteasomal degradation, but the molecular links between these pathways are poorly characterized.Here we show that autophagy is enhanced by the silencing of genes encoding various proteasome subunits (?, ? or regulatory) in larval fat body cells. Proteasome inactivation induces canonical autophagy, as it depends on core autophagy genes Atg1, Vps34, Atg9, Atg4 and Atg12. Large-scale accumulation of aggregates containing p62 and ubiquitinated proteins is observed in proteasome RNAi cells. Importantly, overexpressed Atg8a reporters are captured into the cytoplasmic aggregates, but these do not represent autophagosomes. Loss of p62 does not block autophagy upregulation upon proteasome impairment, suggesting that compensatory autophagy is not simply due to the buildup of excess cargo. One of the best characterized substrates of UPS is the ? subunit of hypoxia-inducible transcription factor 1 (HIF-1?), which is continuously degraded by the proteasome during normoxic conditions. Hypoxia is a known trigger of autophagy in mammalian cells, and we show that genetic activation of hypoxia signaling also induces autophagy in Drosophila. Moreover, we find that proteasome inactivation-induced autophagy requires sima, the Drosophila ortholog of HIF-1?.We have characterized proteasome inactivation- and hypoxia signaling-induced autophagy in the commonly used larval Drosophila fat body model. Activation of both autophagy and hypoxia signaling was implicated in various cancers, and mutations affecting genes encoding UPS enzymes have recently been suggested to cause renal cancer. Our studies identify a novel genetic link that may play an important role in that context, as HIF-1?/sima may contribute to upregulation of autophagy by impaired proteasomal activity.

Project description:BackgroundHypoxia has long been considered as a hallmark of solid tumors and is closely associated with tumor progression. Circular RNAs (circRNAs) have been identified as a critical modulator in various cancers. However, the connections between hypoxia and circRNAs are largely unknown.MethodsHere, we investigated the expression profile of circRNAs in breast cancer (BC) MCF-7 cells under hypoxia and normoxia using microarray. We identified a novel hypoxia-responsive circRNA named circWSB1, whose expression pattern, potential diagnostic value and prognostic significance were assessed by qRT-PCR and in situ hybridization. Loss- and gain-of-function investigations in vivo and in vitro were performed to determine the biological functions of circWSB1. Mechanistically, chromatin immunoprecipitation and dual luciferase reporter assays were carried out to analyze the biogenesis of circWSB1. Furthermore, biotin-labeled RNA pull-down, mass spectrometry, RNA immunoprecipitation, fluorescent in situ hybridization, RNA electrophoretic mobility shift, deletion-mapping, co-immunoprecipitation assays and rescue experiments were applied to investigate the interaction between circWSB1 and Ubiquitin-specific peptidase 10 (USP10) as well as the relationship between USP10 and p53.ResultsWe found that the expression of circWSB1 was significantly upregulated in BC tissues and correlated with poor clinical outcomes, which might serve as an independent prognostic factor for BC patients. Ectopic expression of circWSB1 promoted the proliferation of BC cell in vitro and in vivo. Mechanistically, circWSB1 was transcriptionally upregulated by HIF1α in response to hypoxia and could competitively bind to deubiquitinase USP10 to prevent the access of p53 to USP10 in BC cells, leading to degradation of p53 and tumor progression of BC.ConclusionsTaken together, our findings disclose a novel mechanism that hypoxia-inducible circWSB1 could interact with USP10 to attenuate USP10 mediated p53 stabilization and promote the progression of BC, providing an alternative prognostic biomarker and therapeutic target for BC.

Dataset Information

Hypoxia-induced proteasomal degradation of DBC1 by SIAH2 in breast cancer progression.

Publications

Hypoxia-induced proteasomal degradation of DBC1 by SIAH2 in breast cancer progression.

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