Selective inhibition of histone deacetylase 6 (HDAC6) induces DNA damage and sensitizes transformed cells to anticancer agents Journal Article

   


Authors: Namdar, M.; Perez, G.; Ngo, L.; Marks, P. A.
Article Title: Selective inhibition of histone deacetylase 6 (HDAC6) induces DNA damage and sensitizes transformed cells to anticancer agents
Abstract: Histone deacetylase 6 (HDAC6) is structurally and functionally unique among the 11 human zinc-dependent histone deacetylases. Here we show that chemical inhibition with the HDAC6-selective inhibitor tubacin significantly enhances cell death induced by the topoisomerase II inhibitors etoposide and doxorubicin and the pan- HDAC inhibitor SAHA (vorinostat) in transformed cells (LNCaP, MCF- 7), an effect not observed in normal cells (human foreskin fibroblast cells). The inactive analogue of tubacin, nil-tubacin, does not sensitize transformed cells to these anticancer agents. Further, we show that down-regulation of HDAC6 expression by shRNA in LNCaP cells enhances cell death induced by etoposide, doxorubicin, and SAHA. Tubacin in combination with SAHA or etoposide is more potent than either drug alone in activating the intrinsic apoptotic pathway in transformed cells, as evidenced by an increase in PARP cleavage and partial inhibition of this effect by the pan-caspase inhibitor Z-VAD-fmk. HDAC6 inhibition with tubacin induces the accumulation of γH2AX, an early marker of DNA double-strand breaks. Tubacin enhances DNA damage induced by etoposide or SAHA as indicated by increased accumulation of γH2AX and activation of the checkpoint kinase Chk2. Tubacin induces the expression of DDIT3 (CHOP/GADD153), a transcription factor up-regulated in response to cellular stress. DDIT3 induction is further increased when tubacin is combined with SAHA. These findings point to mechanisms by which HDAC6-selective inhibition can enhance the efficacy of certain anti-cancer agents in transformed cells.
Keywords: controlled study; protein expression; unclassified drug; human cell; histone deacetylase inhibitor; doxorubicin; antineoplastic agents; conference paper; antineoplastic agent; dna replication; cell death; dna damage; apoptosis; enzyme inhibition; etoposide; neoplasm proteins; down-regulation; cytotoxicity; drug potency; enzyme activation; drug screening assays, antitumor; enzyme activity; caspases; cell line, tumor; phosphorylation; cell transformation, neoplastic; drug synergism; gene expression regulation, neoplastic; dna; double stranded dna; cell transformation; protein-serine-threonine kinases; vorinostat; histone deacetylase inhibitors; hydroxamic acids; protein induction; double stranded dna break; checkpoint kinase 2; down regulation; upregulation; up-regulation; γh2ax; histone h2ax; histones; histone deacetylases; short hairpin rna; g1 phase; anilides; sensitization; topoisomerase ii inhibitors; cell strain lncap; cell stress; tubacin; gamma histone h2ax; chk2; growth arrest and dna damage inducible protein 153; histone deacetylase 6; ddit3/chop/gadd153
Journal Title: Proceedings of the National Academy of Sciences of the United States of America
Volume: 107
Issue: 46
ISSN: 0027-8424
Publisher: National Academy of Sciences  
Date Published: 2010-11-16
Start Page: 20003
End Page: 20008
Language: English
DOI: 10.1073/pnas.1013754107
PUBMED: 21037108
PROVIDER: scopus
PMCID: PMC2993347
DOI/URL:

http://www.scopus.com/inward/record.url?eid=2-s2.0-78650575875&partnerID=40&md5=d42c048b30f4bc8674e533caad67544b
Notes: --- - "Export Date: 20 April 2011" - "CODEN: PNASA" - "Source: Scopus"
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MSK Authors
  1. Mandana J Namdar
    1 Namdar
  2. Lang Ngo
    27 Ngo
  3. Gisela Venta-Perez
    23 Venta-Perez
  4. Paul Marks
    186 Marks
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