Theranostics 2019; 9(26):8392-8408. doi:10.7150/thno.36838 This issue Cite

Research Paper

CACYBP Enhances Cytoplasmic Retention of P27Kip1 to Promote Hepatocellular Carcinoma Progression in the Absence of RNF41 Mediated Degradation

Yi-Fan Lian1*, Yan-Lin Huang1,2*, Yao-Jun Zhang3*, Dong-Mei Chen1, Jia-Liang Wang1, Huan Wei1, Yan-Hua Bi1, Zhi-Wu Jiang4, Peng Li4, Min-Shan Chen3✉, Yue-Hua Huang1,2✉

1. Guangdong Provincial Key Laboratory of Liver Disease Research, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
2. Department of Infectious Diseases, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
3. Department of Hepatobiliary Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China
4. Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
*These authors contributed equally to this work.

Citation:
Lian YF, Huang YL, Zhang YJ, Chen DM, Wang JL, Wei H, Bi YH, Jiang ZW, Li P, Chen MS, Huang YH. CACYBP Enhances Cytoplasmic Retention of P27Kip1 to Promote Hepatocellular Carcinoma Progression in the Absence of RNF41 Mediated Degradation. Theranostics 2019; 9(26):8392-8408. doi:10.7150/thno.36838. https://www.thno.org/v09p8392.htm
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Abstract

Graphic abstract

Calcyclin-binding protein (CACYBP) is a multi-ligand protein implicated in the progression of various human cancers. However, its function in hepatocellular carcinoma (HCC) remains unknown.

Methods: The expression of CACYBP and RNF41 (RING finger protein 41) in HCC cancer and adjacent non-tumor tissues was detected by immunohistochemistry. CCK-8 assays, colony formation assays, flow cytometry detection and xenograft models were used to evaluate the impact of CACYBP expression on HCC cell growth, apoptosis and cell cycle regulation. Immunoprecipitation and ubiquitination assays were performed to determine how RNF41 regulates CACYBP. The regulatory mechanism of RNF41-CACYBP signaling axis on P27Kip1 was investigated by western blotting and immunofluorescence.

Results: CACYBP was highly expressed and associated with poor prognosis in HCC. CACYBP expression was required for HCC cell growth in vitro and in vivo. Moreover, we identified RNF41 as a specific binding partner of CACYBP at exogenous and endogenous levels. RNF41 recruited CACYBP by its C-terminal substrate binding domain, subsequently ubiquitinating CACYBP and promoting its degradation in both proteasome- and lysosome-dependent pathways. In HCC tissues, RNF41 expression was reduced and conferred a negative correlation with CACYBP expression. Mechanistically, CACYBP overexpression stimulated the Ser10, Thr157 and Thr198 phosphorylation of P27Kip1 and its cytoplasmic retention, and RNF41 co-expression attenuated this phenomenon. CACYBP depletion led to decreased levels of cyclin D1, cyclin A2, CDK2 and CDK4, causing a typical cell cycle arrest at G1/S phase and increasing apoptosis in HCC cells. P27Kip1-S10D but not P27Kip1-S10A reconstitution rescued partially the cell cycle function and apoptotic feature after CACYBP depletion.

Conclusion: Our findings provide novel insights into the functional role and regulatory mechanism of CACYBP in HCC.

Keywords: Hepatocellular carcinoma, CACYBP/SIP, RNF41/Nrdp1, P27Kip1, Cell cycle


Citation styles

APA
Lian, Y.F., Huang, Y.L., Zhang, Y.J., Chen, D.M., Wang, J.L., Wei, H., Bi, Y.H., Jiang, Z.W., Li, P., Chen, M.S., Huang, Y.H. (2019). CACYBP Enhances Cytoplasmic Retention of P27Kip1 to Promote Hepatocellular Carcinoma Progression in the Absence of RNF41 Mediated Degradation. Theranostics, 9(26), 8392-8408. https://doi.org/10.7150/thno.36838.

ACS
Lian, Y.F.; Huang, Y.L.; Zhang, Y.J.; Chen, D.M.; Wang, J.L.; Wei, H.; Bi, Y.H.; Jiang, Z.W.; Li, P.; Chen, M.S.; Huang, Y.H. CACYBP Enhances Cytoplasmic Retention of P27Kip1 to Promote Hepatocellular Carcinoma Progression in the Absence of RNF41 Mediated Degradation. Theranostics 2019, 9 (26), 8392-8408. DOI: 10.7150/thno.36838.

NLM
Lian YF, Huang YL, Zhang YJ, Chen DM, Wang JL, Wei H, Bi YH, Jiang ZW, Li P, Chen MS, Huang YH. CACYBP Enhances Cytoplasmic Retention of P27Kip1 to Promote Hepatocellular Carcinoma Progression in the Absence of RNF41 Mediated Degradation. Theranostics 2019; 9(26):8392-8408. doi:10.7150/thno.36838. https://www.thno.org/v09p8392.htm

CSE
Lian YF, Huang YL, Zhang YJ, Chen DM, Wang JL, Wei H, Bi YH, Jiang ZW, Li P, Chen MS, Huang YH. 2019. CACYBP Enhances Cytoplasmic Retention of P27Kip1 to Promote Hepatocellular Carcinoma Progression in the Absence of RNF41 Mediated Degradation. Theranostics. 9(26):8392-8408.

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