Abstract
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 showthat the NAD1-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.
| Original language | English |
|---|---|
| Pages (from-to) | 1138-1150 |
| Number of pages | 13 |
| Journal | Blood |
| Volume | 127 |
| Issue number | 9 |
| DOIs | |
| Publication status | Published - Mar 3 2016 |
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ASJC Scopus subject areas
- Hematology
- Biochemistry
- Cell Biology
- Immunology
Cite this
Evidence for a role of the histone deacetylase SIRT6 in DNA damage response of multiple myeloma cells. / Cea, Michele; Cagnetta, Antonia; Adamia, Sophia; Acharya, Chirag; Tai, Yu Tzu; Fulciniti, Mariateresa; Ohguchi, Hiroto; Munshi, Aditya; Acharya, Prakrati; Bhasin, Manoj K.; Zhong, Lei; Carrasco, Ruben; Monacelli, Fiammetta; Ballestrero, Alberto; Richardson, Paul; Gobbi, Marco; Lemoli, Roberto M.; Munshi, Nikhil; Hideshima, Teru; Nencioni, Alessio; Chauhan, Dharminder; Anderson, Kenneth C.
In: Blood, Vol. 127, No. 9, 03.03.2016, p. 1138-1150.Research output: Contribution to journal › Article
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TY - JOUR
T1 - Evidence for a role of the histone deacetylase SIRT6 in DNA damage response of multiple myeloma cells
AU - Cea, Michele
AU - Cagnetta, Antonia
AU - Adamia, Sophia
AU - Acharya, Chirag
AU - Tai, Yu Tzu
AU - Fulciniti, Mariateresa
AU - Ohguchi, Hiroto
AU - Munshi, Aditya
AU - Acharya, Prakrati
AU - Bhasin, Manoj K.
AU - Zhong, Lei
AU - Carrasco, Ruben
AU - Monacelli, Fiammetta
AU - Ballestrero, Alberto
AU - Richardson, Paul
AU - Gobbi, Marco
AU - Lemoli, Roberto M.
AU - Munshi, Nikhil
AU - Hideshima, Teru
AU - Nencioni, Alessio
AU - Chauhan, Dharminder
AU - Anderson, Kenneth C.
PY - 2016/3/3
Y1 - 2016/3/3
N2 - 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 showthat the NAD1-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.
AB - 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 showthat the NAD1-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.
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UR - http://www.scopus.com/inward/citedby.url?scp=84960433970&partnerID=8YFLogxK
U2 - 10.1182/blood-2015-06-649970
DO - 10.1182/blood-2015-06-649970
M3 - Article
VL - 127
SP - 1138
EP - 1150
JO - Blood
JF - Blood
SN - 0006-4971
IS - 9
ER -