A SIRT2-Selective Inhibitor Promotes c-Myc Oncoprotein Degradation and Exhibits Broad Anticancer Activity

Publication date: 14 March 2016
Source:Cancer Cell, Volume 29, Issue 3
Author(s): Hui Jing, Jing Hu, Bin He, Yashira L. Negrón Abril, Jack Stupinski, Keren Weiser, Marisa Carbonaro, Ying-Ling Chiang, Teresa Southard, Paraszkevi Giannakakou, Robert S. Weiss, Hening Lin
Targeting sirtuins for cancer treatment has been a topic of debate due to conflicting reports and lack of potent and specific inhibitors. We have developed a thiomyristoyl lysine compound, TM, as a potent SIRT2-specific inhibitor with a broad anticancer effect in various human cancer cells and mouse models of breast cancer. Mechanistically, SIRT2 inhibition promotes c-Myc ubiquitination and degradation. The anticancer effect of TM correlates with its ability to decrease c-Myc level. TM had limited effects on non-cancerous cells and tumor-free mice, suggesting that cancer cells have an increased dependency on SIRT2 that can be exploited for therapeutic benefit. Our studies demonstrate that SIRT2-selective inhibitors are promising anticancer agents and may represent a general strategy to target certain c-Myc-driven cancers.

Teaser

Jing et al. develop a thiomyristoyl lysine compound, TM, as a potent SIRT2-specific inhibitor with broad anticancer activity but little effect on non-cancerous cells. SIRT2 inhibition promotes c-Myc ubiquitination and degradation, suggesting the therapeutic potential of TM to target certain c-Myc-driven cancers.


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