Inhibition of SIRT1 Limits Self-Renewal and Oncogenesis by Inducing Senescence of Liver Cancer Stem Cells

Purpose: Cancer stem cells (CSCs) have been considered involving in tumorigenesis, local recurrence, and therapeutic drug resistance of hepatocellular carcinoma (HCC). To investi-gate novel and effective methods for targeting hepatic CSCs is crucial for a permanent cure of liver cancer. Methods: The expression level of SIRT1 was detected in CSCs of HCC tissues and cancer cell lines. Expression of CSC markers, the self-renewal and tumorigenic ability of liver CSCs were analyzed with SIRT1 inhibition. Cellular senescence-related markers were used to detect CSCs senescence after inhibition of SIRT1. Results: SIRT1 was highly expressed in CSCs of HCC cell lines and human HCC tissues. In vitro study revealed that decreasing of SIRT1 level significantly downregulated the stemness-associated genes of liver CSCs and reduced the CSC stemness properties. Also, down-regulated SIRT1 suppressed liver CSCs proliferation by decreasing their self-renewal abil-ities. Furthermore, CSCs with decreased SIRT1 expression showed limited tumorigenicity and formed smaller HCC tumor in vivo. And SIRT1 decreased CSCs became more suscep-tible to chemotherapeutic drugs. Mechanistically, SIRT1 decreased CSCs became senescence through the activation of p53-p21 and p16 pathway. The data further indicated that the tumor formed from SIRT1-knockdown CSCs exhibited higher senescence-associated beta-galactosidase (SA-beta-Gal) activity but lower proliferative capacity. Conclusion: Taken together, these findings pointed that induction of senescence in liver CSCs is an effective tumor suppression method for HCC, and SIRT1 may be served as a promising target for HCC treatment.

Automated summary

The study showed that inhibiting SIRT1 can reduce the stemness properties of liver CSCs, suppress their proliferation, and make them more susceptible to chemotherapeutic drugs. Additionally, CSCs with decreased SIRT1 expression had limited tumorigenicity in vivo and entered senescence through the activation of the p53-p21 and p16 pathways.