Sirtuin 6 (SIRT6) is a member of the NAD+ dependent histone deacetylase (HDAC) family. HDACs play an important role in epigenetic regulation of gene expression, which is counteracted by histone acetyl-transferase (HAT). HDACs remove acetyl-group at lysine residue of histone tail, and change the conformation of chromatin complex, which eventually regulates transcription activity in of various cancer cells. SIRT6 is reported to be a site specific deacetylase acting at histone H3K9 and H3K56, but very few studies on the regulation of SIRT6 expression have been reported. Cyclic AMP (cAMP) signaling system regulates a variety of cellular responses including metabolism, gene expression, proliferation and death. Therefore, we studied the effect of cAMP signaling system on the expression of SIRT6 and its underlying mechanism in lung cancer cells. Stimulatory heterotrimeric GTP-binding proteins (Gαs) are activated by various ligand-bound receptors and stimulate adenylate cyclase to activate cAMP signaling system. Expression of constitutive active Gαs (GαsQL) decreased SIRT6 protein level without change in its mRNA level in H1299 lung cancer cells. GαsQL expression accelerated proteasomal degradation of SIRT6, resulting in a decreased half-life of the protein from 2.2 h to 1.2 h. SIRT6 expression was also decreased by forskolin (adenylate cyclase activator), but increased by H89 (PKA inhibitor). These results indicate that cAMP signaling system decreases SIRT6 expression by accelerating proteasomal degradation of SIRT6 expression via PKA-dependent pathway in lung cancer cells. This finding suggests that cAMP signaling system can contribute epigenetic regulation of cancer-related gene expression by modifying SIRT6 expression.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-279. doi:1538-7445.AM2012-LB-279