Identification of a cellularly active SIRT6 allosteric activator

Area of Science:

• Biochemistry
• Molecular Biology
• Oncology

Background:

• SIRT6, a deacetylase, suppresses tumors but is often underexpressed in cancers.
• SIRT6 regulates histone modifications, specifically deacetylation of H3K9ac and H3K56ac.
• Low SIRT6 expression is linked to various cancer types, including hepatocellular carcinoma (HCC).

Purpose of the Study:

• To identify and characterize a novel activator of SIRT6.
• To investigate the therapeutic potential of pharmacological SIRT6 activation in HCC treatment.
• To explore the mechanism by which SIRT6 activation impacts HCC cell proliferation.

Main Methods:

• Identification and characterization of MDL-800, a selective SIRT6 activator.
• Assay of MDL-800's effect on SIRT6 deacetylase activity in vitro and in HCC cells.
• Analysis of global H3K9ac and H3K56ac levels following MDL-800 treatment.
• Assessment of MDL-800's impact on HCC cell proliferation and cell-cycle progression.
• Evaluation of MDL-800 efficacy in a HCC tumor xenograft model.

Main Results:

• MDL-800 significantly increased SIRT6 deacetylase activity (up to 22-fold) by allosteric binding.
• MDL-800 treatment led to a global decrease in H3K9ac and H3K56ac levels in HCC cells.
• MDL-800 inhibited HCC cell proliferation through SIRT6-dependent cell-cycle arrest.
• MDL-800 demonstrated efficacy in reducing tumor size in a HCC xenograft model.

Conclusions:

• Pharmacological activation of SIRT6 using MDL-800 is a promising therapeutic strategy for HCC.
• MDL-800 represents a first-in-class small-molecule activator for studying SIRT6 functions.
• Targeting SIRT6 deacetylation offers a novel approach for liver cancer treatment.