Hepatocellular carcinoma (HCC) remains challenging due to the lack of efficient therapy. Promoting degradation of certain cancer drivers has become an innovative therapy. The nuclear transcription factor sine oculis homeobox 1 (SIX1) is a key driver for the progression of HCC. Here, we explored the molecular mechanisms of ubiquitination of SIX1 and whether targeting SIX1 degradation might represent a potential strategy for HCC therapy. Through detecting the ubiquitination level of SIX1 in clinical HCC tissues and analyzing TCGA and GEPIA databases, we found that ubiquitin specific peptidase 1 (USP1), a deubiquitinating enzyme, contributed to the lower ubiquitination and high protein level of SIX1 in HCC tissues. In HepG2 and Hep3B cells, activation of EGFR-AKT signaling pathway promoted the expression of USP1 and the stability of its substrates, including SIX1 and ribosomal protein S16 (RPS16). In contrast, suppression of EGFR with gefitinib or knockdown of USP1 restrained EGF-elevated levels of SIX1 and RPS16. We further revealed that SNS-023 (formerly known as BMS-387032) induced degradation of SIX1 and RPS16, whereas this process was reversed by reactivation of EGFR-AKT pathway or overexpression of USP1. Consequently, inactivation of the EGFR-AKT-USP1 axis with SNS-032 led to cell cycle arrest, apoptosis, and suppression of cell proliferation and migration in HCC. Moreover, we showed that sorafenib combined with SNS-032 or gefitinib synergistically inhibited the growth of Hep3B xenografts in vivo. Overall, we identify that both SIX1 and RPS16 are crucial substrates for the EGFR-AKT-USP1 axis-driven growth of HCC, suggesting a potential anti-HCC strategy from a novel perspective.
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This work was supported by National Natural Science Foundation of China (82002481, 82072810), the open research funds from the Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People’s Hospital (202011-304, 202011-204), the Science and Technology Program of Guangzhou (202102020931), Natural Science Foundation Research Team of Guangdong Province (2018B030312001), Cultivation Program of National Natural Science Foundation for Distinguished Young Scholars of Guangzhou Medical University (JP2022002), Discipline Construction Funds of Guangzhou Medical University (JCXKJS2021C04, JCXKJS2021D03, and JCXKJS2021D06), Special Fund of Foshan Summit Plan (2020G010) and Guangzhou Key Medical Discipline Construction Project Fund.
The authors declare no competing interests.
The original online version of this article was revised: The statistical symbols are wrong in primary figure. So Fig 1, 3, 4, 5, 6, 7 and Supplementary materials need replacement with the new one.
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Liu, Y., Kong, Wy., Yu, Cf. et al. SNS-023 sensitizes hepatocellular carcinoma to sorafenib by inducing degradation of cancer drivers SIX1 and RPS16. Acta Pharmacol Sin 44, 853–864 (2023). https://doi.org/10.1038/s41401-022-01003-4
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