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

Abstract

Key Points• SIRT6 is highly expressed in multiple myeloma cells and blocks expression of ERKregulated genes.• Targeting SIRT6 enzymatic activity sensitizes multiple myeloma cells to DNAdamaging agents.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 1 -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 the ERK signaling-related gene. By binding to their promoters and deacetylating H3K9 at these sites, SIRT6 downregulates the expression of mitogen-activated protein kinase (MAPK) pathway genes, MAPK signaling, and proliferation. In addition, inactivation of ERK2/p90RSK signaling triggered by high SIRT6 levels increases DNA repair via Chk1 and 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 for both tumorigenesis and the treatment of MM. (Blood. 2016;127(9):1138-1150 IntroductionGenomic instability is a common feature of monoclonal gammopathies, resulting in complex genetic changes associated with disease progression from monoclonal gammopathy of undetermined significance to active multiple myeloma (MM) to plasma cell leukemia.1,2 Although alterations in DNA damage checkpoint proteins are less common (10% to 15%) in blood cancers compared with solid tumors, [3][4][5] MM cells do manifest a dysfunctional DNA-damage response (DDR), a key determinant of their genomic instability. [6][7][8] Identifying proteins and signaling pathways that protect MM cells from cumulative genomic instability may therefore lead to innovative therapeutic opportunities, as exemplified by the clinical efficacy of PARP inhibitors in the context of breast and ovarian tumors lacking functional BRCA1 or BRCA2. 9,10 In MM cells, direct evidence of homozygous loss or mutations in BRCA1/2 or other DDR genes is lacking, but increased DNA repair activity has been reported. 11,12 Thus, identification of adaptive pathways for coping with genomic instability in MM may similarly provide the framework for new therapeutic strategies. Sirtuins (SIRTs) are NAD1 -degrading enzymes involved in a variety of biological processes, ranging from metabolism to lifespan regulation. 13,14 Of the 7 sirtuin family members, only SIRT6 clearly contributes to DNA repair. [15][16][17][18] Consistently, murine SIRT6 knockout cells exhibit genomic instability and hypersensitivity to DNA-damaging agents. 15,17,19 Moreover...

SIRT6: Novel Mechanisms and Links to Aging and Disease

“…SIRT6 copy number is increased in some hematopoietic cancer cell lines [5]. Moreover, elevated SIRT6 expression occurs in cases of Multiple Myeloma (MM) and some solid tumors, and in some instances is associated with poor clinical outcome [47-52]. Thus, SIRT6 could have oncogenic rather than tumor suppressive functions in certain contexts.…”

“…Alternatively, SIRT6 overexpression in these cancers could represent a compensatory mechanism to oppose tumor progression. Indeed, increased SIRT6 expression in MM cells inhibits tumor cell proliferation via H3K9 deacetylation and transcriptional repression of pro-proliferative MAPK/ERK target genes, and enhances SIRT6-dependent DNA damage response functions (See Figure 3d-e, Box 2) [47]. These findings suggest that modulation of SIRT6 activity in cancer cells varies with tumor type and cancer stage, and elucidating the complex mechanisms and pleiotropic effects of SIRT6 in cancer cell biology will be crucial for attempts to target SIRT6 for cancer therapy.…”

The multifaceted influence of histone deacetylases on DNA damage signalling and DNA repair

“…Some HDACs are upregulated in colorectal, stomach, oesophagus, breast, ovary, lung, pancreas, thyroid, prostate, melanoma, neuroblastoma and oral cancers (5–28), while some SIRTs are upregulated in myeloma, breast, liver and thyroid cancers (29–32). Downregulation of HDAC4 in glioblastoma (33), SIRT1 and SIRT6 in colorectal cancer (34,35) and SIRT6 in pancreas cancer (35) has also been reported.…”

The role of SIRT6 in tumors

“…In multiple myeloma (MM), SIRT6 is highly expressed as adaptive response to genomic stability, and its overexpression is associated to proliferation and poor prognosis. 22 Cea et al 22 demonstrated in vitro and in a human MM xenograft model that SIRT6 down-regulates the expression of ERK signaling-related genes and suppresses the activity of ETS-domain transcription factor (ELK1), increasing DNA repair level via Chk1 (a critical messenger of the genome integrity checkpoints involved in the evolution of human cancer 23 ), and conferring resistance to DNA-damaging agents. In this scenario, the paper by Cagnetta et al 24 studies the biological relevance and the genomic instability and poor prognosis associated with the mRNA upregulation of SIRT6 in the acute myeloid leukemia (AML) cells compared with low SIRT6 levels detected in normal CD34 + hematopoietic progenitors.…”