SOCS1 Blocks G1-S Transition in Hepatocellular Carcinoma by Reducing the Stability of the CyclinD1/CDK4 Complex in the Nucleus

Abstract

Background: Inhibitors of the CDK family of proteins have been approved for the treatment of a variety of tumours; however, the use of this type of drug alone is often ineffective and elicits adverse side effects. The development of new drugs administered in combination with CDK inhibitors is expected to improve the therapeutic effect. Methods: We identified the function of suppressor of cytokine signalling 1 (SOCS1) in hepatocellular carcinoma (HCC) cell models and the xenograft mouse model. The molecular mechanism of SOCS1 regulating cell proliferation was proved through transcriptome sequencing, western blot and Co-IP. Findings: When SOCS1 expression was artificially upregulated, HCC cell lines were arrested at the G1-S transition in the cell cycle. Interestingly, during this process, total CyclinD1 protein increased, but the effective proportion decreased. We found that the deficiency of CyclinD1 in the nucleus is probably due to the decrease in the stability of nuclear CyclinD1 caused by the ubiquitin-based degradation of P21 and P27, thus inhibiting the progression of the cell cycle to S phase. After P21 expression was increased, the levels of the component that inactivates CyclinD1 decreased as expected. It showed that P21 has a partial promoting effect on cancer. Interpretation: As a tumour inhibitory factor in HCC, SOCS1 is a good indicator of prognosis, tumour size and long-term survival after resection. SOCS1 is expected to become a drug target in combined with CDK family inhibitors. Funding Statement: Innovative Research Groups of National Natural Science Foundation of China (No. 81721091), Major program of National Natural Science Foundation of China (No.91542205), National S&T Major Project (No. 2017ZX10203205), Zhejiang International Science and Technology Cooperation Project (No.2016C04003), National Natural Science Foundation of China (No. 81773070). Declaration of Interests: The authors declare that they have no competing interests. Ethics Approval Statement: The study protocol was approved by the ethics committee of the First Affiliated Hospital of Zhejiang University. All experiments containing animals according to protocols approved by Animal Care and Use Committee of Zhejiang University.