MITF Expression Predicts Therapeutic Vulnerability to p300 Inhibition in Human Melanoma.

Abstract

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.

• Authors: Edward Kim, Beth E Zucconi, Muzhou Wu, Sarah E Nocco, David J Meyers, Jean S McGee, Samantha Venkatesh, Daniel L Cohen, Estela C Gonzalez, Byungwoo Ryu, Philip A Cole, Rhoda M Alani
• Journal: Cancer research (Cancer Res) Vol. 79 Issue 10 Pg. 2649-2661 (05 15 2019) ISSN: 1538-7445 [Electronic] United States
• PMID: 30910803 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2019 American Association for Cancer Research.

Chemical References

• Forkhead Box Protein M1
• MITF protein, human
• Microphthalmia-Associated Transcription Factor
• E1A-Associated p300 Protein
• EP300 protein, human
• Histone Acetyltransferases

Topics

• Acetylation
• Cell Cycle (genetics)
• Cell Line, Tumor
• Cell Proliferation (genetics)
• Cellular Senescence (genetics)
• E1A-Associated p300 Protein (genetics)
• Forkhead Box Protein M1 (genetics)
• Gene Expression Regulation, Neoplastic (genetics)
• Histone Acetyltransferases (genetics)
• Humans
• Melanoma (genetics)
• Microphthalmia-Associated Transcription Factor (genetics)