Sirtuin 7 super-enhancer drives epigenomic reprogramming in hepatocarcinogenesis.

Area of Science:

• Oncology
• Epigenetics
• Molecular Biology

Background:

• Hepatocellular carcinoma (HCC) incidence is rising globally.
• Super-enhancers (SEs) are crucial for cell identity but their role in HCC is unclear.
• Data from primary HCC tumors is scarce.

Purpose of the Study:

• To investigate the role of SEs in non-alcoholic fatty liver disease (NAFLD)-associated HCC.
• To identify SE-driven regulatory networks in HCC.
• To explore SIRT7 as a potential therapeutic target in HCC.

Main Methods:

• Chromatin profiling of NAFLD-associated HCC and matched liver tissues.
• Identification and analysis of somatically-acquired SEs and their target genes.
• Functional enrichment analysis of SE-target genes.
• Depletion of SIRT7 SE in hepatoma cells and assessment of tumorigenicity.
• Investigation of SIRT7 and EZH2 interaction.

Main Results:

• Identified ~500 somatically-acquired SEs per HCC patient, enriched for metabolism and chromatin regulators.
• Found consistent SE activation of Sirtuin 7 (SIRT7), leading to H3K18 deacetylation, H3K27me3, and tumor-suppressor gene silencing.
• SIRT7 depletion reversed epigenetic marks, reactivated metabolic/immune genes, and suppressed HCC tumorigenicity in vitro and in vivo.
• Discovered SIRT7 physically interacts with EZH2, and both are co-expressed in HCC.

Conclusions:

• Established a compendium of SEs in NAFLD-associated HCC.
• Uncovered a SIRT7-driven chromatin regulatory network crucial for HCC.
• Identified this network as a potential druggable vulnerability for HCC treatment.