Hypoxia-induced circWSB1 promotes breast cancer progression through destabilizing p53 by interacting with USP10

Abstract

Background Hypoxia 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. Methods Here, 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. Results We 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. Conclusions Taken 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.

Hypoxia-induced exosomal circPDK1 promotes pancreatic cancer glycolysis via c-myc activation by modulating miR-628-3p/BPTF axis and degrading BIN1

“…Functionally, exosomal circPDK1 may significantly promote PC growth, metastasis, and glycolysis both in vitro and in vivo, indicating a tumor-promoting role in PC. Abundant circRNAs are transcriptionally activated by HIF1A under hypoxic conditions, based on exon-derived circRNAs, and their host linear genes would be generated from the same pre-mRNA; besides, circRNA might be modulated by HIF1A through activating transcription of the circRNA host gene [29,30,39]. In fact, the host gene of circPDK1, PDK1 is overexpressed in PC and transcriptionally activated by HIF1A, and parts of specific interactive regions have been verified [40][41][42][43].…”

Noncoding RNAs as sensors of tumor microenvironmental stress

“…Enhanced expression of circDENND4C facilitates glycolysis, migration, and invasion by sponging miR-200b and miR-200c or through the miR-760/GLUT1 axis in breast cancer or in colorectal cancer cells, respectively [ 31 – 33 ]. Overexpressed circWSB1 promotes breast cancer progression via destabilizing p53 by interacting with USP10 [ 34 ]. In addition, it is worth noting that a majority of these hypoxia-responsive ncRNAs are discovered via high-throughput RNA-seq or RNA-microarray.…”

Conducive target range of breast cancer: Hypoxic tumor microenvironment

“…In addition to competitively antagonizing miRNA, circRNA also has other mechanisms to play a role. CircWSB1 was up-regulated by HIF1α transcription and competitively binds to the deubiquitinase USP10, preventing p53 access to USP10 in BC cells, leading to the degradation of p53 and tumor progression of BC ( 108 ). Table 1…”