Related Experiment Video
Updated: May 19, 2026
A 3D Organotypic Melanoma Spheroid Skin Model
Published on: May 18, 2018
Mechanistic and preclinical evaluation of SIRT3 as a therapeutic target in melanoma
Karla B Anaya Aldrete1, Mary A Ndiaye1, Glorimar Guzmán-Pérez1
1Department of Dermatology, University of Wisconsin, Madison, Wisconsin, USA.
Abstract:
Despite advances in targeted inhibitors and immunotherapies, melanoma remains one of the deadliest skin cancers due to high metastatic potential and resistance to current therapies. This underscores a critical need for new, mechanism-based treatment strategies. Sirtuins, a family of class III histone deacetylases, have been implicated by our lab and others in numerous cellular functions, diseases, and cancers including melanoma. Here, we sought to extend our findings on the pro-proliferative role of SIRT3 by: (i) defining downstream mechanisms using PCR array and NanoString gene-expression profiling on CRISPR/Cas9-mediated SIRT3 knockout (KO) in melanoma cells; (ii) assessing effects of siRNA against SIRT3 in patient-derived xenograft (PDX) and BrafV600E/PtenNULL melanoma models; and (iii) evaluating efficacy of SIRT3 inhibitor 4'-Bromo-resveratrol (4'-BR) in PDXes. SIRT3 KO significantly reduced growth and colony formation in A375 and G361 melanoma cells. PCR array and NanoString analysis revealed modulation of key cancer-related signaling molecules. In vivo, siRNA-mediated SIRT3 inhibition in melanoma PDXes and BrafV600E/PtenNULL mice trended toward reduced tumor growth. However, dual SIRT1/SIRT3 inhibition with 4'-BR (50 mg/kg, ip, 2x/week) significantly decreased tumor volume and weight in melanoma PDXes. Overall, our data suggests that targeting SIRT1 and SIRT3 together could offer greater therapeutic benefit and should be validated and optimized.
Insights
Targeting SIRT1 and SIRT3 together shows promise for treating melanoma. Dual inhibition significantly reduced tumor growth in preclinical models, suggesting a new therapeutic strategy for this deadly skin cancer.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Melanoma is a deadly skin cancer with high metastatic potential and resistance to therapies.
- Sirtuins (class III histone deacetylases) are implicated in cancer, including melanoma.
- SIRT3 has a pro-proliferative role in melanoma, necessitating further investigation.
Purpose of the Study:
- To define downstream mechanisms of SIRT3 in melanoma.
- To assess the effects of SIRT3 inhibition in preclinical melanoma models.
- To evaluate the efficacy of a dual SIRT1/SIRT3 inhibitor in melanoma.
Main Methods:
- CRISPR/Cas9-mediated SIRT3 knockout (KO) in melanoma cells.
- PCR array and NanoString gene-expression profiling.
- siRNA-mediated SIRT3 inhibition in patient-derived xenografts (PDX) and genetically engineered mouse models.
- In vivo efficacy study of SIRT3 inhibitor 4'-Bromo-resveratrol (4'-BR) in PDX models.
Main Results:
- SIRT3 KO significantly reduced melanoma cell growth and colony formation.
- Gene-expression profiling revealed modulation of key cancer-related signaling pathways.
- Dual SIRT1/SIRT3 inhibition with 4'-BR significantly decreased tumor volume and weight in melanoma PDX models, while single SIRT3 inhibition showed a trend towards reduced tumor growth.
Conclusions:
- Targeting SIRT3 alone or in combination with SIRT1 may represent a novel therapeutic strategy for melanoma.
- Dual inhibition of SIRT1 and SIRT3 demonstrated significant anti-tumor efficacy in preclinical melanoma models.
- Further validation and optimization of dual SIRT1/SIRT3 inhibition are warranted for melanoma treatment.
