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WSB1 regulates c-Myc expression through β-Catenin signalling and forms a feedforward circuit.

ABSTRACT: The dysregulation of transcription factors is widely associated with tumourigenesis. As the most well-defined transcription factor in multiple types of cancer, c-Myc can transform cells by transactivating various downstream genes. Given that there is no effective way to directly inhibit c-Myc, c-Myc targeting strategies hold great potential for cancer therapy. In this study, we found that WSB1, which has a highly positive correlation with c-Myc in 10 cancer cell lines and clinical samples, is a direct target gene of c-Myc, and can positively regulate c-Myc expression, which forms a feedforward circuit promoting cancer development. RNA sequencing results from Bel-7402 cells confirmed that WSB1 promoted c-Myc expression through the β-Catenin pathway. Mechanistically, WSB1 affected β-Catenin destruction complex-PPP2CA assembly and E3 ubiquitin ligase adaptor β-TRCP recruitment, which inhibited the ubiquitination of β-Catenin and transactivated c-Myc. Of interest, the effect of WSB1 on c-Myc was independent of its E3 ligase activity. Moreover, overexpressing WSB1 in the Bel-7402 xenograft model could further strengthen the tumour-driven effect of c-Myc overexpression. Thus, our findings revealed a novel mechanism involved in tumourigenesis in which the WSB1/c-Myc feedforward circuit played an essential role, highlighting a potential c-Myc intervention strategy in cancer treatment.

ORGANISM(S): Homo sapiens

PROVIDER: GSE182635 | GEO | 2021/10/01

REPOSITORIES: GEO

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Project description:Baicalein, a purified flavonoid compound with defined chemical structure extracted from the dry roots of Scutellaria radix that is a broadly used herb in China, has been proved to possess significant anti-hepatoma activity by inhibiting cell proliferation, invasion, metastasis and inducing apoptosis, autophagy via several cancer-related signaling molecules. In recent years, emerging studies have demonstrated that Chinese medicinal herbs can exert their anti-tumor effects through targeting lncRNAs，such as curcumin, camptothecin, resveratrol，paclitaxel. However, there is still no related report about the effects of baicalein on lncRNA expression profile when it exerts its inhibition on hepatoma tumor growth. To investigate whether the antitumor effect of baicalein is related to its modulation of lncRNA expression in hepatocellular carcinoma (HCC), we profiled the lncRNA expression in HCC cell line Bel-7402 treated with baicalein (0, 40, 80μM) for 24 hours using lncRNA microarray and detected the changes by comparing the lncRNA expression profile of HCC cell line Bel-7402 treated with baicalein (40 and 80 μM) and its DMSO control (0 μM). These findings suggest that modulation of lncRNA expression may be an important mechanism underlying the anti-hepatoma effects of baicalein and lay the groundwork for further investigations. To investigate whether the antitumor effect of baicalein is related to its modulation of lncRNA expression in hepatocellular carcinoma (HCC), we profiled the miRNA expression in HCC cell line Bel-7402 treated with baicalein (0, 40, 80μM) for 24 hours using miRNA microarray and detected the changes by comparing the lncRNA expression profile of HCC cell line Bel-7402 treated with baicalein (40 and 80 μM) and its DMSO control (0 μM). These findings suggest that modulation of lncRNA expression may be an important mechanism underlying the anti-hepatoma effects of baicalein and lay the groundwork for further investigations.

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WSB1 regulates c-Myc expression through β-Catenin signalling and forms a feedforward circuit.

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