Targeting histone deacetylase 6 mediates a dual anti-melanoma effect

Enhanced antitumor immunity and impaired cell proliferation

K. V. Woan, M. Lienlaf, P. Perez-Villaroel, C. Lee, F. Cheng, T. Knox, D. M. Woods, K. Barrios, J. Powers, E. Sahakian, H. W. Wang, J. Canales, D. Marante, K. S.M. Smalley, J. Bergman, E. Seto, A. Kozikowski, J. Pinilla-Ibarz, A. Sarnaik, Esteban Celis & 3 others J. Weber, E. M. Sotomayor, A. Villagra

Research output: Contribution to journalArticle

38 Citations (Scopus)

Abstract

The median survival for metastatic melanoma is in the realm of 8-16 months and there are few therapies that offer significant improvement in overall survival. One of the recent advances in cancer treatment focuses on epigenetic modifiers to alter the survivability and immunogenicity of cancer cells. Our group and others have previously demonstrated that pan-HDAC inhibitors induce apoptosis, cell cycle arrest and changes in the immunogenicity of melanoma cells. Here we interrogated specific HDACs which may be responsible for this effect. We found that both genetic abrogation and pharmacologic inhibition of HDAC6 decreases in vitro proliferation and induces G1 arrest of melanoma cell lines without inducing apoptosis. Moreover, targeting this molecule led to an important upregulation in the expression of tumor associated antigens and MHC class I, suggesting a potential improvement in the immunogenicity of these cells. Of note, this anti-melanoma activity was operative regardless of mutational status of the cells. These effects translated into a pronounced delay of in vivo melanoma tumor growth which was, at least in part, dependent on intact immunity as evidenced by the restoration of tumor growth after CD4+ and CD8+ depletion. Given our findings, we provide the initial rationale for the further development of selective HDAC6 inhibitors as potential therapeutic anti-melanoma agents.

Original languageEnglish (US)
Pages (from-to)1447-1457
Number of pages11
JournalMolecular Oncology
Volume9
Issue number7
DOIs
StatePublished - Aug 1 2015

Fingerprint

Histone Deacetylases
Immunity
Melanoma
Cell Proliferation
Neoplasms
Apoptosis
Histone Deacetylase Inhibitors
Neoplasm Antigens
Growth
Cell Cycle Checkpoints
Epigenomics
Up-Regulation
Cell Line
Therapeutics

Keywords

  • HDAC6
  • Histone deacetylases
  • Melanoma
  • Nexturastat
  • Tubastatin A

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Oncology
  • Cancer Research

Cite this

Targeting histone deacetylase 6 mediates a dual anti-melanoma effect : Enhanced antitumor immunity and impaired cell proliferation. / Woan, K. V.; Lienlaf, M.; Perez-Villaroel, P.; Lee, C.; Cheng, F.; Knox, T.; Woods, D. M.; Barrios, K.; Powers, J.; Sahakian, E.; Wang, H. W.; Canales, J.; Marante, D.; Smalley, K. S.M.; Bergman, J.; Seto, E.; Kozikowski, A.; Pinilla-Ibarz, J.; Sarnaik, A.; Celis, Esteban; Weber, J.; Sotomayor, E. M.; Villagra, A.

In: Molecular Oncology, Vol. 9, No. 7, 01.08.2015, p. 1447-1457.

Research output: Contribution to journalArticle

Woan, KV, Lienlaf, M, Perez-Villaroel, P, Lee, C, Cheng, F, Knox, T, Woods, DM, Barrios, K, Powers, J, Sahakian, E, Wang, HW, Canales, J, Marante, D, Smalley, KSM, Bergman, J, Seto, E, Kozikowski, A, Pinilla-Ibarz, J, Sarnaik, A, Celis, E, Weber, J, Sotomayor, EM & Villagra, A 2015, 'Targeting histone deacetylase 6 mediates a dual anti-melanoma effect: Enhanced antitumor immunity and impaired cell proliferation', Molecular Oncology, vol. 9, no. 7, pp. 1447-1457. https://doi.org/10.1016/j.molonc.2015.04.002
Woan, K. V. ; Lienlaf, M. ; Perez-Villaroel, P. ; Lee, C. ; Cheng, F. ; Knox, T. ; Woods, D. M. ; Barrios, K. ; Powers, J. ; Sahakian, E. ; Wang, H. W. ; Canales, J. ; Marante, D. ; Smalley, K. S.M. ; Bergman, J. ; Seto, E. ; Kozikowski, A. ; Pinilla-Ibarz, J. ; Sarnaik, A. ; Celis, Esteban ; Weber, J. ; Sotomayor, E. M. ; Villagra, A. / Targeting histone deacetylase 6 mediates a dual anti-melanoma effect : Enhanced antitumor immunity and impaired cell proliferation. In: Molecular Oncology. 2015 ; Vol. 9, No. 7. pp. 1447-1457.
@article{19acfcb798ae4e50b70b4f68da31a339,
title = "Targeting histone deacetylase 6 mediates a dual anti-melanoma effect: Enhanced antitumor immunity and impaired cell proliferation",
abstract = "The median survival for metastatic melanoma is in the realm of 8-16 months and there are few therapies that offer significant improvement in overall survival. One of the recent advances in cancer treatment focuses on epigenetic modifiers to alter the survivability and immunogenicity of cancer cells. Our group and others have previously demonstrated that pan-HDAC inhibitors induce apoptosis, cell cycle arrest and changes in the immunogenicity of melanoma cells. Here we interrogated specific HDACs which may be responsible for this effect. We found that both genetic abrogation and pharmacologic inhibition of HDAC6 decreases in vitro proliferation and induces G1 arrest of melanoma cell lines without inducing apoptosis. Moreover, targeting this molecule led to an important upregulation in the expression of tumor associated antigens and MHC class I, suggesting a potential improvement in the immunogenicity of these cells. Of note, this anti-melanoma activity was operative regardless of mutational status of the cells. These effects translated into a pronounced delay of in vivo melanoma tumor growth which was, at least in part, dependent on intact immunity as evidenced by the restoration of tumor growth after CD4+ and CD8+ depletion. Given our findings, we provide the initial rationale for the further development of selective HDAC6 inhibitors as potential therapeutic anti-melanoma agents.",
keywords = "HDAC6, Histone deacetylases, Melanoma, Nexturastat, Tubastatin A",
author = "Woan, {K. V.} and M. Lienlaf and P. Perez-Villaroel and C. Lee and F. Cheng and T. Knox and Woods, {D. M.} and K. Barrios and J. Powers and E. Sahakian and Wang, {H. W.} and J. Canales and D. Marante and Smalley, {K. S.M.} and J. Bergman and E. Seto and A. Kozikowski and J. Pinilla-Ibarz and A. Sarnaik and Esteban Celis and J. Weber and Sotomayor, {E. M.} and A. Villagra",
year = "2015",
month = "8",
day = "1",
doi = "10.1016/j.molonc.2015.04.002",
language = "English (US)",
volume = "9",
pages = "1447--1457",
journal = "Molecular Oncology",
issn = "1574-7891",
publisher = "Elsevier",
number = "7",

}

TY - JOUR

T1 - Targeting histone deacetylase 6 mediates a dual anti-melanoma effect

T2 - Enhanced antitumor immunity and impaired cell proliferation

AU - Woan, K. V.

AU - Lienlaf, M.

AU - Perez-Villaroel, P.

AU - Lee, C.

AU - Cheng, F.

AU - Knox, T.

AU - Woods, D. M.

AU - Barrios, K.

AU - Powers, J.

AU - Sahakian, E.

AU - Wang, H. W.

AU - Canales, J.

AU - Marante, D.

AU - Smalley, K. S.M.

AU - Bergman, J.

AU - Seto, E.

AU - Kozikowski, A.

AU - Pinilla-Ibarz, J.

AU - Sarnaik, A.

AU - Celis, Esteban

AU - Weber, J.

AU - Sotomayor, E. M.

AU - Villagra, A.

PY - 2015/8/1

Y1 - 2015/8/1

N2 - The median survival for metastatic melanoma is in the realm of 8-16 months and there are few therapies that offer significant improvement in overall survival. One of the recent advances in cancer treatment focuses on epigenetic modifiers to alter the survivability and immunogenicity of cancer cells. Our group and others have previously demonstrated that pan-HDAC inhibitors induce apoptosis, cell cycle arrest and changes in the immunogenicity of melanoma cells. Here we interrogated specific HDACs which may be responsible for this effect. We found that both genetic abrogation and pharmacologic inhibition of HDAC6 decreases in vitro proliferation and induces G1 arrest of melanoma cell lines without inducing apoptosis. Moreover, targeting this molecule led to an important upregulation in the expression of tumor associated antigens and MHC class I, suggesting a potential improvement in the immunogenicity of these cells. Of note, this anti-melanoma activity was operative regardless of mutational status of the cells. These effects translated into a pronounced delay of in vivo melanoma tumor growth which was, at least in part, dependent on intact immunity as evidenced by the restoration of tumor growth after CD4+ and CD8+ depletion. Given our findings, we provide the initial rationale for the further development of selective HDAC6 inhibitors as potential therapeutic anti-melanoma agents.

AB - The median survival for metastatic melanoma is in the realm of 8-16 months and there are few therapies that offer significant improvement in overall survival. One of the recent advances in cancer treatment focuses on epigenetic modifiers to alter the survivability and immunogenicity of cancer cells. Our group and others have previously demonstrated that pan-HDAC inhibitors induce apoptosis, cell cycle arrest and changes in the immunogenicity of melanoma cells. Here we interrogated specific HDACs which may be responsible for this effect. We found that both genetic abrogation and pharmacologic inhibition of HDAC6 decreases in vitro proliferation and induces G1 arrest of melanoma cell lines without inducing apoptosis. Moreover, targeting this molecule led to an important upregulation in the expression of tumor associated antigens and MHC class I, suggesting a potential improvement in the immunogenicity of these cells. Of note, this anti-melanoma activity was operative regardless of mutational status of the cells. These effects translated into a pronounced delay of in vivo melanoma tumor growth which was, at least in part, dependent on intact immunity as evidenced by the restoration of tumor growth after CD4+ and CD8+ depletion. Given our findings, we provide the initial rationale for the further development of selective HDAC6 inhibitors as potential therapeutic anti-melanoma agents.

KW - HDAC6

KW - Histone deacetylases

KW - Melanoma

KW - Nexturastat

KW - Tubastatin A

UR - http://www.scopus.com/inward/record.url?scp=84938212386&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84938212386&partnerID=8YFLogxK

U2 - 10.1016/j.molonc.2015.04.002

DO - 10.1016/j.molonc.2015.04.002

M3 - Article

VL - 9

SP - 1447

EP - 1457

JO - Molecular Oncology

JF - Molecular Oncology

SN - 1574-7891

IS - 7

ER -