Essential role of HDAC6 in the regulation of PD-L1 in melanoma

M. Lienlaf, P. Perez-Villarroel, T. Knox, M. Pabon, E. Sahakian, J. Powers, K. V. Woan, C. Lee, F. Cheng, S. Deng, K. S M Smalley, M. Montecino, A. Kozikowski, J. Pinilla-Ibarz, A. Sarnaik, E. Seto, J. Weber, E. M. Sotomayor, A. Villagra

Research output: Contribution to journalArticle

Abstract

Histone deacetylases (HDACs), originally described as histone modifiers, have more recently been demonstrated to target a variety of other proteins unrelated to the chromatin environment. In this context, our present work demonstrates that the pharmacological or genetic abrogation of HDAC6 in primary melanoma samples and cell lines, down-regulates the expression of PD-L1, an important co-stimulatory molecule expressed in cancer cells, which activates the inhibitory regulatory pathway PD-1 in T-cells. Our data suggests that this novel mechanism of PD-L1 regulation is mainly mediated by the influence of HDAC6 over the recruitment and activation of STAT3. Additionally, we observed that selective HDAC6 inhibitors impairs tumor growth and reduce the in vivo expression of several inhibitory check-point molecules and other regulatory pathways involved in immunosurveillance. Most importantly, these results provide a key pre-clinical rationale and justification to further study isotype selective HDAC6 inhibitors as potential immuno-modulatory agents in cancer.

Original languageEnglish (US)
JournalMolecular Oncology
DOIs
StateAccepted/In press - Oct 16 2015
Externally publishedYes

Fingerprint

Melanoma
Immunologic Monitoring
Neoplasms
Histone Deacetylases
Histones
Chromatin
Down-Regulation
Pharmacology
T-Lymphocytes
Cell Line
Growth
Proteins

Keywords

  • HDAC6
  • Histone deacetylases
  • Melanoma
  • Nexturastat
  • PD-L1
  • PP2A
  • STAT3
  • Tubastatin A

ASJC Scopus subject areas

  • Cancer Research
  • Genetics
  • Molecular Medicine

Cite this

Lienlaf, M., Perez-Villarroel, P., Knox, T., Pabon, M., Sahakian, E., Powers, J., ... Villagra, A. (Accepted/In press). Essential role of HDAC6 in the regulation of PD-L1 in melanoma. Molecular Oncology. https://doi.org/10.1016/j.molonc.2015.12.012

Essential role of HDAC6 in the regulation of PD-L1 in melanoma. / Lienlaf, M.; Perez-Villarroel, P.; Knox, T.; Pabon, M.; Sahakian, E.; Powers, J.; Woan, K. V.; Lee, C.; Cheng, F.; Deng, S.; Smalley, K. S M; Montecino, M.; Kozikowski, A.; Pinilla-Ibarz, J.; Sarnaik, A.; Seto, E.; Weber, J.; Sotomayor, E. M.; Villagra, A.

In: Molecular Oncology, 16.10.2015.

Research output: Contribution to journalArticle

Lienlaf, M, Perez-Villarroel, P, Knox, T, Pabon, M, Sahakian, E, Powers, J, Woan, KV, Lee, C, Cheng, F, Deng, S, Smalley, KSM, Montecino, M, Kozikowski, A, Pinilla-Ibarz, J, Sarnaik, A, Seto, E, Weber, J, Sotomayor, EM & Villagra, A 2015, 'Essential role of HDAC6 in the regulation of PD-L1 in melanoma', Molecular Oncology. https://doi.org/10.1016/j.molonc.2015.12.012
Lienlaf M, Perez-Villarroel P, Knox T, Pabon M, Sahakian E, Powers J et al. Essential role of HDAC6 in the regulation of PD-L1 in melanoma. Molecular Oncology. 2015 Oct 16. https://doi.org/10.1016/j.molonc.2015.12.012
Lienlaf, M. ; Perez-Villarroel, P. ; Knox, T. ; Pabon, M. ; Sahakian, E. ; Powers, J. ; Woan, K. V. ; Lee, C. ; Cheng, F. ; Deng, S. ; Smalley, K. S M ; Montecino, M. ; Kozikowski, A. ; Pinilla-Ibarz, J. ; Sarnaik, A. ; Seto, E. ; Weber, J. ; Sotomayor, E. M. ; Villagra, A. / Essential role of HDAC6 in the regulation of PD-L1 in melanoma. In: Molecular Oncology. 2015.
@article{08735b9282984ba0b1bbb88712246a8e,
title = "Essential role of HDAC6 in the regulation of PD-L1 in melanoma",
abstract = "Histone deacetylases (HDACs), originally described as histone modifiers, have more recently been demonstrated to target a variety of other proteins unrelated to the chromatin environment. In this context, our present work demonstrates that the pharmacological or genetic abrogation of HDAC6 in primary melanoma samples and cell lines, down-regulates the expression of PD-L1, an important co-stimulatory molecule expressed in cancer cells, which activates the inhibitory regulatory pathway PD-1 in T-cells. Our data suggests that this novel mechanism of PD-L1 regulation is mainly mediated by the influence of HDAC6 over the recruitment and activation of STAT3. Additionally, we observed that selective HDAC6 inhibitors impairs tumor growth and reduce the in vivo expression of several inhibitory check-point molecules and other regulatory pathways involved in immunosurveillance. Most importantly, these results provide a key pre-clinical rationale and justification to further study isotype selective HDAC6 inhibitors as potential immuno-modulatory agents in cancer.",
keywords = "HDAC6, Histone deacetylases, Melanoma, Nexturastat, PD-L1, PP2A, STAT3, Tubastatin A",
author = "M. Lienlaf and P. Perez-Villarroel and T. Knox and M. Pabon and E. Sahakian and J. Powers and Woan, {K. V.} and C. Lee and F. Cheng and S. Deng and Smalley, {K. S M} and M. Montecino and A. Kozikowski and J. Pinilla-Ibarz and A. Sarnaik and E. Seto and J. Weber and Sotomayor, {E. M.} and A. Villagra",
year = "2015",
month = "10",
day = "16",
doi = "10.1016/j.molonc.2015.12.012",
language = "English (US)",
journal = "Molecular Oncology",
issn = "1574-7891",
publisher = "Elsevier",

}

TY - JOUR

T1 - Essential role of HDAC6 in the regulation of PD-L1 in melanoma

AU - Lienlaf, M.

AU - Perez-Villarroel, P.

AU - Knox, T.

AU - Pabon, M.

AU - Sahakian, E.

AU - Powers, J.

AU - Woan, K. V.

AU - Lee, C.

AU - Cheng, F.

AU - Deng, S.

AU - Smalley, K. S M

AU - Montecino, M.

AU - Kozikowski, A.

AU - Pinilla-Ibarz, J.

AU - Sarnaik, A.

AU - Seto, E.

AU - Weber, J.

AU - Sotomayor, E. M.

AU - Villagra, A.

PY - 2015/10/16

Y1 - 2015/10/16

N2 - Histone deacetylases (HDACs), originally described as histone modifiers, have more recently been demonstrated to target a variety of other proteins unrelated to the chromatin environment. In this context, our present work demonstrates that the pharmacological or genetic abrogation of HDAC6 in primary melanoma samples and cell lines, down-regulates the expression of PD-L1, an important co-stimulatory molecule expressed in cancer cells, which activates the inhibitory regulatory pathway PD-1 in T-cells. Our data suggests that this novel mechanism of PD-L1 regulation is mainly mediated by the influence of HDAC6 over the recruitment and activation of STAT3. Additionally, we observed that selective HDAC6 inhibitors impairs tumor growth and reduce the in vivo expression of several inhibitory check-point molecules and other regulatory pathways involved in immunosurveillance. Most importantly, these results provide a key pre-clinical rationale and justification to further study isotype selective HDAC6 inhibitors as potential immuno-modulatory agents in cancer.

AB - Histone deacetylases (HDACs), originally described as histone modifiers, have more recently been demonstrated to target a variety of other proteins unrelated to the chromatin environment. In this context, our present work demonstrates that the pharmacological or genetic abrogation of HDAC6 in primary melanoma samples and cell lines, down-regulates the expression of PD-L1, an important co-stimulatory molecule expressed in cancer cells, which activates the inhibitory regulatory pathway PD-1 in T-cells. Our data suggests that this novel mechanism of PD-L1 regulation is mainly mediated by the influence of HDAC6 over the recruitment and activation of STAT3. Additionally, we observed that selective HDAC6 inhibitors impairs tumor growth and reduce the in vivo expression of several inhibitory check-point molecules and other regulatory pathways involved in immunosurveillance. Most importantly, these results provide a key pre-clinical rationale and justification to further study isotype selective HDAC6 inhibitors as potential immuno-modulatory agents in cancer.

KW - HDAC6

KW - Histone deacetylases

KW - Melanoma

KW - Nexturastat

KW - PD-L1

KW - PP2A

KW - STAT3

KW - Tubastatin A

UR - http://www.scopus.com/inward/record.url?scp=84954288063&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84954288063&partnerID=8YFLogxK

U2 - 10.1016/j.molonc.2015.12.012

DO - 10.1016/j.molonc.2015.12.012

M3 - Article

JO - Molecular Oncology

JF - Molecular Oncology

SN - 1574-7891

ER -