CRHBP is degraded via autophagy and exerts anti-hepatocellular carcinoma effects by reducing cyclin B2 expression and dissociating cyclin B2-CDK1 complex.

Zhiwei Wang, Mingxing Li, Yuanfeng Liu, Zhentao Qiao, Ling Yang, Bo Liu, Tao Bai

Cancer gene therapy 2022 Aug

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Autophagy is the predominant self-eating catabolic pathway activated in response to nutrient starvation and hypoxia within the microenvironment of varied malignancies, including hepatocellular carcinoma (HCC). SQSTM1/p62 links its cargos to autophagosomes for degradation, and reportedly acts as a contributor for hepatocarcinogenesis. Five GEO gene microarrays identified corticotropin releasing hormone (CRH) binding protein (CRHBP) as a significantly downregulated gene in HCC (log2 Fold change < -3 and p < 0.001), and an earlier human interactome study indicated that CRHBP may interact with p62. This study aimed to explore (1) the role of CRHBP in HCC development, and (2) whether p62-mediated autophagy was responsible for low CRHBP expression within HCC tissue. Following functional experiments first revealed an anti-proliferative, anti-metastatic, and anti-angiogenic role of CRHBP in HCC cells (Huh-7, Li-7 and HCCLM3) and xenografts. CRHBP negatively regulated cyclin B2 expression, and dissociated cyclin B2-CDK1 complex in HCC cells, thereby leading to cell cycle arrest at G2 phase. To simulate HCC microenvironment in vitro, Huh-7 cells were incubated in Earle's Balanced Salt Solution (nutrient starvation) or exposed to 1% O2 (hypoxic exposure). In addition to activating autophagy, nutrient starvation and hypoxic exposure also induced CRHBP degradation. Interestingly, CRHBP was demonstrated as a novel cargo targeted by p62 for degradation in autophagosomes. Blocking autophagy with 3-MA, chloroquine or siSQSTM1 prevented CRHBP degradation in HCC cells. Collectively, our study uncovers a role for CRHBP in retarding HCC development, reducing cyclin B2 expression and impairing cyclin B2-CDK1 interaction. CRHBP downregulation in HCC may attribute to p62-mediated autophagy. © 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.

Citation

Zhiwei Wang, Mingxing Li, Yuanfeng Liu, Zhentao Qiao, Ling Yang, Bo Liu, Tao Bai. CRHBP is degraded via autophagy and exerts anti-hepatocellular carcinoma effects by reducing cyclin B2 expression and dissociating cyclin B2-CDK1 complex. Cancer gene therapy. 2022 Aug;29(8-9):1217-1227