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A Novel Transgenic Mouse Model Implicates Sirt2 as a Promoter of Hepatocellular Carcinoma
Alexandra V Schmidt1, Satdarshan P Monga2,3,4, Edward V Prochownik2,5
1Division of Genetic and Genomic Medicine, Department of Pediatrics, University of Pittsburgh School of Medicine, University of Pittsburgh, Pittsburgh, PA 15260, USA.
Abstract:
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer deaths globally. Incidence rates are steadily increasing, creating an unmet need for new therapeutic options. Recently, the inhibition of sirtuin-2 (Sirt2) was proposed as a potential treatment for HCC, despite contradictory findings of its role as both a tumor promoter and suppressor in vitro. Sirt2 functions as a lysine deacetylase enzyme. However, little is known about its biological influence, despite its implication in several age-related diseases. This study evaluated Sirt2's role in HCC in vivo using an inducible c-MYC transgene in Sirt2/ and Sirt2-/- mice. Sirt2-/- HCC mice had smaller, less proliferative, and more differentiated liver tumors, suggesting that Sirt2 functions as a tumor promoter in this context. Furthermore, Sirt2-/- HCCs had significantly less c-MYC oncoprotein and reduction in c-MYC nuclear localization. The RNA-seq showed that only three genes were significantly dysregulated due to loss of Sirt2, suggesting the underlying mechanism is due to Sirt2-mediated changes in the acetylome, and that the therapeutic inhibition of Sirt2 would not perturb the oncogenic transcriptome. The findings of this study suggest that Sirt2 inhibition could be a promising molecular target for slowing HCC growth.
Insights
Sirtuin-2 (Sirt2) promotes hepatocellular carcinoma (HCC) growth. Inhibiting Sirt2 in mice reduced tumor size and proliferation, suggesting Sirt2 is a promising therapeutic target for liver cancer.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Hepatocellular carcinoma (HCC) incidence is rising globally, necessitating novel therapeutic strategies.
- The precise role of sirtuin-2 (Sirt2), a lysine deacetylase, in HCC remains unclear, with conflicting in vitro data.
- Understanding Sirt2's in vivo function is crucial for evaluating its therapeutic potential in liver cancer.
Purpose of the Study:
- To investigate the in vivo role of Sirt2 in hepatocellular carcinoma development and progression.
- To determine if Sirt2 acts as a tumor promoter or suppressor in the context of HCC.
- To explore the molecular mechanisms underlying Sirt2's influence on HCC growth.
Main Methods:
- Utilized an inducible c-MYC transgene model in Sirt2 knockout (Sirt2-/-) and wild-type mice.
- Assessed tumor size, proliferation, and differentiation in Sirt2-/- HCC mice compared to controls.
- Analyzed c-MYC oncoprotein levels, nuclear localization, and global gene expression (RNA-seq) in Sirt2-/- HCCs.
Main Results:
- Sirt2-/- HCC mice exhibited smaller, less proliferative, and more differentiated liver tumors.
- Loss of Sirt2 led to decreased c-MYC oncoprotein levels and reduced nuclear localization.
- RNA-sequencing revealed minimal transcriptional changes, suggesting Sirt2 impacts HCC via epigenetic modifications (acetylome).
Conclusions:
- Sirtuin-2 (Sirt2) functions as a tumor promoter in hepatocellular carcinoma in vivo.
- Therapeutic inhibition of Sirt2 may represent a viable strategy for slowing HCC progression.
- Targeting Sirt2 could offer a novel approach without broadly disrupting the oncogenic transcriptome.
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