Deciphering the role of SIRT6 in suppressing the AMPK-mTOR-TFEB axis: regulation of autophagy activation in HCC.

Abstract

Sirtuin 6 (SIRT6), belong to the NAD-dependent class III protein deacetylase family, is implicated in cancer development through a multifaceted role. While it has been identified with both tumor-suppressive and tumor-promoting roles in Hepatocellular carcinoma (HCC), there remains considerable debate regarding its exact function. The specific molecular mechanisms driving its tumor-suppressive effects in HCC remains poorly understood. In this study, we mechanistically identified a novel pathway involving AMP-activated protein kinase (AMPK), mammalian target of rapamycin (mTOR), and transcription factor EB (TFEB): upregulation of SIRT6 enhances AMPK activity and suppresses mTOR activation, leading to TFEB nuclear translocation and the subsequent induction of autophagy. Importantly, our study provides the first evidence that SIRT6 induces the translocation of TFEB into the nucleus, facilitating autophagy. Intriguingly, SIRT6 silencing counteracted the effects of mTOR inhibitors on TFEB and autophagy, suggesting that SIRT6 probably activates lysosome function via an AMPK-mTOR-TFEB axis in HCC. Our in vivo experiments bolster our findings, demonstrating that SIRT6 effectively suppressed HCC tumor growth and metastasis. Overall, our research provides compelling evidence that SIRT6 functions as a tumor suppressor in HCC, offering a valuable therapeutic mechanism for treating HCC and paving the way for a promising avenue in future HCC treatment. Schematic illustration of SIRT6's role in hepatocellular carcinoma. Proposing a model to elucidate the regulatory mechanism of SIRT6-AMPK-mTOR-TFEB signaling axis in orchestrating autophagy activation within hepatocellular carcinoma. Phosphorylation of AMPK by SIRT6 leads to the inhibition of mTOR and its downstream targets. This modulation influences TFEB, promoting its translocation into the nucleus and triggering autophagy activation. This intricate cascade is marked by a significant increase in substrate degradation and the formation of autophagic bilayers, ultimately culminating in the suppression of cell proliferation and the augmentation of cell death.