PMID- 30910803
OWN - NLM
STAT- In-Data-Review
LR  - 20190518
IS  - 1538-7445 (Electronic)
IS  - 0008-5472 (Linking)
VI  - 79
IP  - 10
DP  - 2019 May 15
TI  - MITF Expression Predicts Therapeutic Vulnerability to p300 Inhibition in Human
      Melanoma.
PG  - 2649-2661
LID - 10.1158/0008-5472.CAN-18-2331 [doi]
AB  - Histone modifications, largely regulated by histone acetyltransferases (HAT) and 
      histone deacetylases, have been recognized as major regulatory mechanisms
      governing human diseases, including cancer. Despite significant effort and recent
      advances, the mechanism by which the HAT and transcriptional coactivator p300
      mediates tumorigenesis remains unclear. Here, we use a genetic and chemical
      approach to identify the microphthalmia-associated transcription factor (MITF) as
      a critical downstream target of p300 driving human melanoma growth. Direct
      transcriptional control of MITF by p300-dependent histone acetylation within
      proximal gene regulatory regions was coupled to cellular proliferation,
      suggesting a significant growth regulatory axis. Further analysis revealed
      forkhead box M1 (FOXM1) as a key effector of the p300-MITF axis driving cell
      growth that is selectively activated in human melanomas. Targeted chemical
      inhibition of p300 acetyltransferase activity using a potent and selective
      catalytic p300/CBP inhibitor demonstrated significant growth inhibitory effects
      in melanoma cells expressing high levels of MITF. Collectively, these data
      confirm the critical role of the p300-MITF-FOXM1 axis in melanoma and support
      p300 as a promising novel epigenetic therapeutic target in human melanoma.
      SIGNIFICANCE: These results show that MITF is a major downstream target of p300
      in human melanoma whose expression is predictive of melanoma response to
      small-molecule inhibition of p300 HAT activity.
CI  - (c)2019 American Association for Cancer Research.
FAU - Kim, Edward
AU  - Kim E
AD  - Department of Dermatology, Boston University School of Medicine, Boston,
      Massachusetts.
FAU - Zucconi, Beth E
AU  - Zucconi BE
AD  - Division of Genetics, Department of Medicine, Brigham and Women's Hospital,
      Boston, Massachusetts.
AD  - Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical
      School, Boston, Massachusetts.
FAU - Wu, Muzhou
AU  - Wu M
AD  - Department of Dermatology, Boston University School of Medicine, Boston,
      Massachusetts.
FAU - Nocco, Sarah E
AU  - Nocco SE
AD  - Department of Dermatology, Boston University School of Medicine, Boston,
      Massachusetts.
FAU - Meyers, David J
AU  - Meyers DJ
AD  - Department of Pharmacology & Molecular Sciences, Johns Hopkins School of
      Medicine, Baltimore, Maryland.
FAU - McGee, Jean S
AU  - McGee JS
AD  - Department of Dermatology, Boston University School of Medicine, Boston,
      Massachusetts.
FAU - Venkatesh, Samantha
AU  - Venkatesh S
AD  - Department of Dermatology, Boston University School of Medicine, Boston,
      Massachusetts.
FAU - Cohen, Daniel L
AU  - Cohen DL
AD  - Department of Dermatology, Boston University School of Medicine, Boston,
      Massachusetts.
FAU - Gonzalez, Estela C
AU  - Gonzalez EC
AD  - Department of Dermatology, Boston University School of Medicine, Boston,
      Massachusetts.
FAU - Ryu, Byungwoo
AU  - Ryu B
AUID- ORCID: https://orcid.org/0000-0001-6334-6787
AD  - Department of Dermatology, Boston University School of Medicine, Boston,
      Massachusetts.
FAU - Cole, Philip A
AU  - Cole PA
AD  - Division of Genetics, Department of Medicine, Brigham and Women's Hospital,
      Boston, Massachusetts. alani@bu.edu pacole@bwh.harvard.edu.
AD  - Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical
      School, Boston, Massachusetts.
FAU - Alani, Rhoda M
AU  - Alani RM
AD  - Department of Dermatology, Boston University School of Medicine, Boston,
      Massachusetts. alani@bu.edu pacole@bwh.harvard.edu.
LA  - eng
GR  - R01 GM062437/GM/NIGMS NIH HHS/United States
GR  - R37 GM062437/GM/NIGMS NIH HHS/United States
GR  - UL1 TR001079/TR/NCATS NIH HHS/United States
PT  - Journal Article
DEP - 20190325
PL  - United States
TA  - Cancer Res
JT  - Cancer research
JID - 2984705R
PMC - PMC6522293
MID - NIHMS1525740
EDAT- 2019/03/27 06:00
MHDA- 2019/03/27 06:00
CRDT- 2019/03/27 06:00
PMCR- 2020/05/15 00:00
PHST- 2018/07/30 00:00 [received]
PHST- 2018/12/27 00:00 [revised]
PHST- 2019/03/21 00:00 [accepted]
PHST- 2020/05/15 00:00 [pmc-release]
PHST- 2019/03/27 06:00 [pubmed]
PHST- 2019/03/27 06:00 [medline]
PHST- 2019/03/27 06:00 [entrez]
AID - 0008-5472.CAN-18-2331 [pii]
AID - 10.1158/0008-5472.CAN-18-2331 [doi]
PST - ppublish
SO  - Cancer Res. 2019 May 15;79(10):2649-2661. doi: 10.1158/0008-5472.CAN-18-2331.
      Epub 2019 Mar 25.