Targeting Lineage-specific MITF Pathway in Human Melanoma Cell Lines by A-485, the Selective Small-molecule Inhibitor of p300/CBP

Mol Cancer Ther. 2018 Dec;17(12):2543-2550. doi: 10.1158/1535-7163.MCT-18-0511. Epub 2018 Sep 28.

Abstract

Metastatic melanoma is responsible for approximately 80% of deaths from skin cancer. Microphthalmia-associated transcription factor (MITF) is a melanocyte-specific transcription factor that plays an important role in the differentiation, proliferation, and survival of melanocytes as well as in melanoma oncogenesis. MITF is amplified in approximately 15% of patients with metastatic melanoma. However, no small-molecule inhibitors of MITF currently exist. MITF was shown to associate with p300/CBP, members of the KAT3 family of histone acetyltransferase. p300 and CREB-binding protein (p300/CBP) regulate a wide range of cellular events such as senescence, apoptosis, cell cycle, DNA damage response, and cellular differentiation. p300/CBP act as transcriptional coactivators for multiple proteins in cancers, including oncogenic transcription factors such as MITF. In this study, we showed that our novel p300/CBP catalytic inhibitor, A-485, induces senescence in multiple melanoma cell lines, similar to silencing expression of EP300 (encodes p300) or MITF We did not observe apoptosis and increase invasiveness upon A-485 treatment. A-485 regulates the expression of MITF and its downstream signature genes in melanoma cell lines undergoing senescence. In addition, expression and copy number of MITF is significantly higher in melanoma cell lines that undergo A-485-induced senescence than resistant cell lines. Finally, we showed that A-485 inhibits histone-H3 acetylation but did not displace p300 at promoters of MITF and its putative downstream genes. Taken together, we provide evidence that p300/CBP inhibition suppressed the melanoma-driven transcription factor, MITF, and could be further exploited as a potential therapy for treating melanoma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • CREB-Binding Protein / antagonists & inhibitors*
  • CREB-Binding Protein / metabolism
  • Cell Line, Tumor
  • Cell Lineage* / drug effects
  • Cell Proliferation / drug effects
  • Cellular Senescence / drug effects
  • DNA Copy Number Variations / genetics
  • E1A-Associated p300 Protein / antagonists & inhibitors*
  • E1A-Associated p300 Protein / metabolism
  • Gene Expression Regulation, Neoplastic / drug effects
  • Heterocyclic Compounds, 4 or More Rings / chemistry
  • Heterocyclic Compounds, 4 or More Rings / pharmacology*
  • Histones / metabolism
  • Humans
  • Melanoma / genetics
  • Melanoma / pathology*
  • Microphthalmia-Associated Transcription Factor / metabolism*
  • Promoter Regions, Genetic / genetics
  • Signal Transduction / drug effects*
  • Small Molecule Libraries / pharmacology*

Substances

  • A-485 compound
  • Heterocyclic Compounds, 4 or More Rings
  • Histones
  • Microphthalmia-Associated Transcription Factor
  • Small Molecule Libraries
  • CREB-Binding Protein
  • CREBBP protein, human
  • E1A-Associated p300 Protein
  • EP300 protein, human