Evidence for a role of the histone deacetylase SIRT6 in DNA damage response of multiple myeloma cells

摘要

Multiple Myeloma (MM) is characterized by a highly unstable genome, with aneuploidy observed in nearly all patients. The mechanism causing this karyotypic instability is largely unknown, but recent observations have correlated these abnormalities with dysfunctional DNA damage response. Here we show that the NAD(+)-dependent deacetylase SIRT6 is highly expressed in MM cells, as an adaptive response, to genomic stability and that high SIRT6 levels are associated with adverse prognosis. Mechanistically, SIRT6 interacts with the transcription factor ELK1 and with ERK signaling-related gene. By binding to their promoters and deacetylating H3K9 at these sites, SIRT6 downregulates the expression of MAPK pathway genes, MAPK-signaling, and proliferation. In addition, inactivation of ERK2/p90RSK signaling triggered by high SIRT6 levels increases DNA repair via Chk1, confers resistance to DNA damage. Using genetic and biochemical studies in vitro and, in human MM xenograft models, we show that SIRT6 depletion both enhances proliferation and confers sensitization to DNA damaging agents. Our findings therefore provide insights into the functional interplay between SIRT6 and DNA repair mechanisms, with implications both for tumorigenesis and treatment of MM.