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

Michele Cea, Antonia Cagnetta, Sophia Adamia, Chirag Acharya, Yu Tzu Tai, Mariateresa Fulciniti, Hiroto Ohguchi, Aditya Munshi, Prakrati Acharya, Manoj K. Bhasin, Lei Zhong, Ruben Carrasco, Fiammetta Monacelli, Alberto Ballestrero, Paul Richardson, Marco Gobbi, Roberto M. Lemoli, Nikhil Munshi, Teru Hideshima, Alessio Nencioni & 2 others Dharminder Chauhan, Kenneth C. Anderson

Research output: Contribution to journalArticle

24 Citations (Scopus)

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 languageEnglish
Pages (from-to)1138-1150
Number of pages13
JournalBlood
Volume127
Issue number9
DOIs
Publication statusPublished - Mar 3 2016

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Histone Deacetylases
Multiple Myeloma
DNA Damage
DNA
Mitogen-Activated Protein Kinases
DNA Repair
Genes
Repair
Genomic Instability
Aneuploidy
Heterografts
Molecular Biology
Carcinogenesis
Transcription Factors
Down-Regulation
Genome
Therapeutics

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

Cea, M., Cagnetta, A., Adamia, S., Acharya, C., Tai, Y. T., Fulciniti, M., ... Anderson, K. C. (2016). Evidence for a role of the histone deacetylase SIRT6 in DNA damage response of multiple myeloma cells. Blood, 127(9), 1138-1150. https://doi.org/10.1182/blood-2015-06-649970

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 journalArticle

Cea, M, Cagnetta, A, Adamia, S, Acharya, C, Tai, YT, Fulciniti, M, Ohguchi, H, Munshi, A, Acharya, P, Bhasin, MK, Zhong, L, Carrasco, R, Monacelli, F, Ballestrero, A, Richardson, P, Gobbi, M, Lemoli, RM, Munshi, N, Hideshima, T, Nencioni, A, Chauhan, D & Anderson, KC 2016, 'Evidence for a role of the histone deacetylase SIRT6 in DNA damage response of multiple myeloma cells', Blood, vol. 127, no. 9, pp. 1138-1150. https://doi.org/10.1182/blood-2015-06-649970
Cea M, Cagnetta A, Adamia S, Acharya C, Tai YT, Fulciniti M et al. Evidence for a role of the histone deacetylase SIRT6 in DNA damage response of multiple myeloma cells. Blood. 2016 Mar 3;127(9):1138-1150. https://doi.org/10.1182/blood-2015-06-649970
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. / Evidence for a role of the histone deacetylase SIRT6 in DNA damage response of multiple myeloma cells. In: Blood. 2016 ; Vol. 127, No. 9. pp. 1138-1150.
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AU - Cagnetta, Antonia

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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.

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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.

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