Abstract
Optimal therapeutic strategies for liver cancer patients remain challenging due to the high recurrence rate after surgical resection and chemotherapy resistance. Emerging evidence has shown that epigenetic factor SIRT7 is involved in various aspects of cancer biology, while inactive SIRT7 reverses human cancer phenotype and suppresses tumor growth. In the present study, we predicted the SIRT7 structure by using the fold recognition (or threading) method and performed structure-based virtual screening to develop specific SIRT7 inhibitor by docking 939319 structurally diverse compounds with SIRT proteins. Compounds with high affinities to SIRT7 but low affinities to other SIRT proteins were chosen as candidates of specific SIRT7 inhibitor. Our leading compounds 2800Z and 40569Z showed strong interaction with SIRT7 protein, and specifically inhibited SIRT7 deacetylation activity in vitro. Our docking results also revealed that ARG-120, TRP-126, and HIS-187 were critical sites responsible for interaction of SIRT7 with small molecules. Mutations in the aforementioned sites significantly abolished interaction and inhibitory effects of compounds to SIRT7. In addition, in vivo data indicated that compounds 2800Z and 40569Z were able to induce apoptosis and increase chemosensitivity to sorafenib in human liver cancer. Our findings demonstrated targeting SIRT7 may offer novel therapeutic options for cancer management, and the value of compounds 2800Z and 40569Z as chemical probes for the study of SIRT7 biological functions as well as starting leads for the development of new therapeutic options against liver cancer.
Highlights
Liver cancer ranks sixth in all cancer incidence and third in cancer motility worldwide, with more than 900,000 new cases reported in 2020 (Siegel et al, 2020; Sung et al, 2021)
A combination therapy with sorafenib and immune checkpoint inhibitor has been approved as first-line therapy for advanced liver cancer, and the results indicated the progression free survival (PFS) is prolonged compared to sorafenib monotherapy (Dyhl-Polk et al, 2021)
We have previously identified that elevated SIRT7 expression is associated with chemoresistance in human liver cancer, and pan-SIRT inhibitor enhances chemosensitivity to doxorubicin, which suggested SIRT7 may serve as a therapeutic target of liver cancer (Zhao et al, 2019)
Summary
Liver cancer ranks sixth in all cancer incidence and third in cancer motility worldwide, with more than 900,000 new cases reported in 2020 (Siegel et al, 2020; Sung et al, 2021). Age-specified studies have revealed that liver cancer incidence among young persons is significantly increased in recent years (Miller et al, 2020). Advanced liver cancer is possibly the most aggressive cancer type which remained clinically challenging to manage due to the low responsiveness to therapy and the high recurrence rate (Bruix et al, 2021). While systemic radiotherapy and chemotherapy are the options for advanced liver cancer, they often show very poor responses (European Association for the Study of the Liver, 2018; Heimbach et al, 2018). Liver cancer is refractory to chemotherapy as it acquires drug resistance and rapidly develops intrahepatic recurrence and distant metastasis (Llovet et al, 2015; Mlynarsky et al, 2015). There are still urgent needs to improve our understanding of the molecular mechanisms that underlie liver cancer malignancy, which will potentiate the mechanism-based translational strategy for future therapeutic development against liver cancer
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