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ARID1A-mutated ovarian cancers depend on HDAC6 activity.

Publication ,  Journal Article
Bitler, BG; Wu, S; Park, PH; Hai, Y; Aird, KM; Wang, Y; Zhai, Y; Kossenkov, AV; Vara-Ailor, A; Rauscher, FJ; Zou, W; Speicher, DW; Cho, KR ...
Published in: Nat Cell Biol
August 2017

ARID1A, encoding a subunit of the SWI/SNF chromatin-remodelling complex, is the most frequently mutated epigenetic regulator across all human cancers. ARID1A and TP53 mutations are typically mutually exclusive. Therapeutic approaches that correlate with this genetic characteristic remain to be explored. Here, we show that HDAC6 activity is essential in ARID1A-mutated ovarian cancers. Inhibition of HDAC6 activity using a clinically applicable small-molecule inhibitor significantly improved the survival of mice bearing ARID1A-mutated tumours. This correlated with the suppression of growth and dissemination of ARID1A-mutated, but not wild-type, tumours. The dependence on HDAC6 activity in ARID1A-mutated cells correlated with a direct transcriptional repression of HDAC6 by ARID1A. HDAC6 inhibition selectively promoted apoptosis of ARID1A-mutated cells. HDAC6 directly deacetylates Lys120 of p53, a pro-apoptotic post-translational modification. Thus, ARID1A mutation inactivates the apoptosis-promoting function of p53 by upregulating HDAC6. Together, these results indicate that pharmacological inhibition of HDAC6 is a therapeutic strategy for ARID1A-mutated cancers.

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Published In

Nat Cell Biol

DOI

EISSN

1476-4679

Publication Date

August 2017

Volume

19

Issue

8

Start / End Page

962 / 973

Location

England

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Tumor Suppressor Protein p53
  • Tumor Cells, Cultured
  • Tumor Burden
  • Transfection
  • Transcription, Genetic
  • Transcription Factors
  • Signal Transduction
  • RNA Interference
  • Protein Processing, Post-Translational
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Bitler, B. G., Wu, S., Park, P. H., Hai, Y., Aird, K. M., Wang, Y., … Zhang, R. (2017). ARID1A-mutated ovarian cancers depend on HDAC6 activity. Nat Cell Biol, 19(8), 962–973. https://doi.org/10.1038/ncb3582
Bitler, Benjamin G., Shuai Wu, Pyoung Hwa Park, Yang Hai, Katherine M. Aird, Yemin Wang, Yali Zhai, et al. “ARID1A-mutated ovarian cancers depend on HDAC6 activity.Nat Cell Biol 19, no. 8 (August 2017): 962–73. https://doi.org/10.1038/ncb3582.
Bitler BG, Wu S, Park PH, Hai Y, Aird KM, Wang Y, et al. ARID1A-mutated ovarian cancers depend on HDAC6 activity. Nat Cell Biol. 2017 Aug;19(8):962–73.
Bitler, Benjamin G., et al. “ARID1A-mutated ovarian cancers depend on HDAC6 activity.Nat Cell Biol, vol. 19, no. 8, Aug. 2017, pp. 962–73. Pubmed, doi:10.1038/ncb3582.
Bitler BG, Wu S, Park PH, Hai Y, Aird KM, Wang Y, Zhai Y, Kossenkov AV, Vara-Ailor A, Rauscher FJ, Zou W, Speicher DW, Huntsman DG, Conejo-Garcia JR, Cho KR, Christianson DW, Zhang R. ARID1A-mutated ovarian cancers depend on HDAC6 activity. Nat Cell Biol. 2017 Aug;19(8):962–973.

Published In

Nat Cell Biol

DOI

EISSN

1476-4679

Publication Date

August 2017

Volume

19

Issue

8

Start / End Page

962 / 973

Location

England

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Tumor Suppressor Protein p53
  • Tumor Cells, Cultured
  • Tumor Burden
  • Transfection
  • Transcription, Genetic
  • Transcription Factors
  • Signal Transduction
  • RNA Interference
  • Protein Processing, Post-Translational