Targeting the deacetylase SIRT6 unveils spliceosome deregulation as exploitable vulnerability for aggressive myeloma

SIRT6 is a NAD + -consuming deacetylase with different abilities, including genomic stability and chromatin accessibility regulation. 1 Importantly, it plays a controversial role in cancer, acting as a tumor suppressor or oncogene depending on the tumors. 2 Such a pleiotropic effect gave rise to extensive efforts to understand the cellular mechanisms by which SIRT6 upsets each cancer speci fi cally. 3-11 We previously reported that multiple myeloma (MM) cells exhibit high levels of SIRT6 in response to their genomic instability. Indeed, SIRT6, by downregulating the expression of extracellular signal-regulated kinase signaling – related genes, suppresses ETS-domain transcription factor (ELK1) activity and increases DNA repair levels via Chk1, resulting in DNA-damaging agents ’ resistance. 12 Here, we investigated the role of SIRT6 in MM by focusing on its relationship with the splicing machinery. We initially

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