Wisconsin Department of Veterans Affairs 5I01CX002210-06

Role of sirtuin 6 in melanoma development and progression

This award funds research on the role of sirtuin 6 (SIRT6) in melanoma development and progression, focusing on molecular pathways involving miR-34a, SIRT6, and NOTCH1. The study aims to develop novel inhibitors for melanoma management, addressing drug resistance in Veterans.

Description

Malignant melanoma is one of the deadliest forms of cancer among Veterans, and the existing therapeutic options have not been fully effective in melanoma management, primarily owing to acquired drug resistance. Therefore, novel target-based approaches are needed for the management of this neoplasm. The mammalian sirtuins belong to a family of seven members (SIRT1 – SIRT7) with NAD+-dependent protein deacetylase and/or ADP-ribosyltransferase activities, which play critical roles in important cellular processes, and are involved in a variety of diseases, including cancer. We have an ongoing program to determine the roles and functional significance of sirtuins in melanoma. Our published and preliminary data has shown a pro-proliferative role of SIRT6 in melanoma in vitro and in vivo. Aberrant expression of SIRT6 has been shown to enhance melanoma growth through an autophagy-dependent manner. Further, our ongoing active VA Merit funding has provided compelling data suggesting that SIRT6 has a pro-proliferative role in melanoma and can serve as a target for melanoma management via its small molecule inhibition. However, an understanding of the mechanisms of the biological actions of SIRT6 in melanoma is far from complete. This may lead to the identification of additional strategies for melanoma management. Further, NOTCH1 is a promising therapeutic target, which is considered as a primary oncogenic factor in melanoma and linked with its metastasis. Thus, development of efficacious novel inhibitors of SIRT6 and NOTCH1 is needed for potential future use against melanoma (and other cancers). Interestingly, SIRT6 and NOTCH1 were found to be the target gene of the micro-RNA (miR)-34a. Importantly, miR-34a is shown to be significantly downregulated in melanoma tissues. The study aims to test the hypothesis that the miR-34a-SIRT6-NOTCH1 axis plays a critical role in melanoma development and progression, and that novel inhibitors identified via virtual screening may be useful for melanoma management.

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