PMID- 30987999
OWN - NLM
STAT- In-Data-Review
LR  - 20190610
IS  - 1538-7445 (Electronic)
IS  - 0008-5472 (Linking)
VI  - 79
IP  - 11
DP  - 2019 Jun 1
TI  - HDAC8 Regulates a Stress Response Pathway in Melanoma to Mediate Escape from BRAF
      Inhibitor Therapy.
PG  - 2947-2961
LID - 10.1158/0008-5472.CAN-19-0040 [doi]
AB  - Melanoma cells have the ability to switch to a dedifferentiated, invasive
      phenotype in response to multiple stimuli. Here, we show that exposure of
      melanomas to multiple stresses including BRAF-MEK inhibitor therapy, hypoxia, and
      UV irradiation leads to an increase in histone deacetylase 8 (HDAC8) activity and
      the adoption of a drug-resistant phenotype. Mass spectrometry-based
      phosphoproteomics implicated HDAC8 in the regulation of MAPK and AP-1 signaling. 
      Introduction of HDAC8 into drug-naive melanoma cells conveyed resistance both in 
      vitro and in vivo. HDAC8-mediated BRAF inhibitor resistance was mediated via
      receptor tyrosine kinase activation, leading to MAPK signaling. Although HDACs
      function at the histone level, they also regulate nonhistone substrates, and
      introduction of HDAC8 decreased the acetylation of c-Jun, increasing its
      transcriptional activity and enriching for an AP-1 gene signature. Mutation of
      the putative c-Jun acetylation site at lysine 273 increased transcriptional
      activation of c-Jun in melanoma cells and conveyed resistance to BRAF inhibition.
      In vivo xenograft studies confirmed the key role of HDAC8 in therapeutic
      adaptation, with both nonselective and HDAC8-specific inhibitors enhancing the
      durability of BRAF inhibitor therapy. Our studies demonstrate that HDAC8-specific
      inhibitors limit the adaptation of melanoma cells to multiple stresses including 
      BRAF-MEK inhibition. SIGNIFICANCE: This study provides evidence that HDAC8 drives
      transcriptional plasticity in melanoma cells in response to a range of stresses
      through direct deacetylation of c-Jun.Graphical Abstract:
      http://cancerres.aacrjournals.org/content/canres/79/11/2947/F1.large.jpg.
CI  - (c)2019 American Association for Cancer Research.
FAU - Emmons, Michael F
AU  - Emmons MF
AD  - The Department of Tumor Biology, The Moffitt Cancer Center and Research
      Institute, Tampa, Florida.
FAU - Faiao-Flores, Fernanda
AU  - Faiao-Flores F
AD  - The Department of Tumor Biology, The Moffitt Cancer Center and Research
      Institute, Tampa, Florida.
FAU - Sharma, Ritin
AU  - Sharma R
AUID- ORCID: https://orcid.org/0000-0001-8365-9916
AD  - The Department of Molecular Oncology, The Moffitt Cancer Center and Research
      Institute, Tampa, Florida.
FAU - Thapa, Ram
AU  - Thapa R
AD  - Department of Bioinformatics and Biostatistics, The Moffitt Cancer Center and
      Research Institute, Tampa, Florida.
FAU - Messina, Jane L
AU  - Messina JL
AUID- ORCID: https://orcid.org/0000-0002-0332-0224
AD  - The Department of Cutaneous Oncology, The Moffitt Cancer Center and Research
      Institute, Tampa, Florida.
FAU - Becker, Jurgen C
AU  - Becker JC
AUID- ORCID: https://orcid.org/0000-0001-9183-653X
AD  - Department of Translational Skin Cancer Research, German Cancer Consortium
      (DKTK), University Hospital Essen, Essen, Germany.
FAU - Schadendorf, Dirk
AU  - Schadendorf D
AUID- ORCID: https://orcid.org/0000-0003-3524-7858
AD  - Department of Translational Skin Cancer Research, German Cancer Consortium
      (DKTK), University Hospital Essen, Essen, Germany.
FAU - Seto, Edward
AU  - Seto E
AD  - George Washington University, Washington, D.C.
FAU - Sondak, Vernon K
AU  - Sondak VK
AD  - The Department of Cutaneous Oncology, The Moffitt Cancer Center and Research
      Institute, Tampa, Florida.
FAU - Koomen, John M
AU  - Koomen JM
AUID- ORCID: https://orcid.org/0000-0002-3818-1762
AD  - The Department of Molecular Oncology, The Moffitt Cancer Center and Research
      Institute, Tampa, Florida.
FAU - Chen, Yian A
AU  - Chen YA
AD  - Department of Bioinformatics and Biostatistics, The Moffitt Cancer Center and
      Research Institute, Tampa, Florida.
FAU - Lau, Eric K
AU  - Lau EK
AD  - The Department of Tumor Biology, The Moffitt Cancer Center and Research
      Institute, Tampa, Florida.
AD  - The Department of Cutaneous Oncology, The Moffitt Cancer Center and Research
      Institute, Tampa, Florida.
FAU - Wan, Lixin
AU  - Wan L
AD  - The Department of Molecular Oncology, The Moffitt Cancer Center and Research
      Institute, Tampa, Florida.
FAU - Licht, Jonathan D
AU  - Licht JD
AUID- ORCID: https://orcid.org/0000-0002-3942-1369
AD  - The University of Florida Health Cancer Center, Gainesville, Florida.
FAU - Smalley, Keiran S M
AU  - Smalley KSM
AD  - The Department of Tumor Biology, The Moffitt Cancer Center and Research
      Institute, Tampa, Florida. keiran.smalley@moffitt.org.
AD  - The Department of Cutaneous Oncology, The Moffitt Cancer Center and Research
      Institute, Tampa, Florida.
LA  - eng
GR  - P30 CA076292/CA/NCI NIH HHS/United States
GR  - P50 CA168536/CA/NCI NIH HHS/United States
GR  - R21 CA198550/CA/NCI NIH HHS/United States
GR  - R21 CA216756/CA/NCI NIH HHS/United States
PT  - Journal Article
DEP - 20190415
PL  - United States
TA  - Cancer Res
JT  - Cancer research
JID - 2984705R
PMC - PMC6548652
MID - NIHMS1527336
EDAT- 2019/04/17 06:00
MHDA- 2019/04/17 06:00
CRDT- 2019/04/17 06:00
PMCR- 2020/06/01 00:00
PHST- 2019/01/03 00:00 [received]
PHST- 2019/03/01 00:00 [revised]
PHST- 2019/04/10 00:00 [accepted]
PHST- 2020/06/01 00:00 [pmc-release]
PHST- 2019/04/17 06:00 [pubmed]
PHST- 2019/04/17 06:00 [medline]
PHST- 2019/04/17 06:00 [entrez]
AID - 0008-5472.CAN-19-0040 [pii]
AID - 10.1158/0008-5472.CAN-19-0040 [doi]
PST - ppublish
SO  - Cancer Res. 2019 Jun 1;79(11):2947-2961. doi: 10.1158/0008-5472.CAN-19-0040. Epub
      2019 Apr 15.