Dataset Information

MITF Expression Predicts Therapeutic Vulnerability to p300 Inhibition in Human Melanoma

ABSTRACT: Histone modifications, largely regulated by histone acetyltransferases (HATs) and histone deacetylases (HDACs) have been recognized as major regulatory mechanisms governing human diseases including cancer. Despite significant effort and recent advances, the mechanism by which the p300 transcriptional coactivator 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. We find that direct transcriptional control of MITF by p300-dependent histone acetylation within proximal gene regulatory regions is 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, which is selectively activated in human melanomas. Targeted chemical inhibition of p300 histone acetyltransferase activity using a potent and selective catalytic p300/CBP inhibitor confirmed the critical role of the p300-MITF-FOXM1 axis in melanoma and demonstrated significant growth inhibitory effects in melanoma cells expressing high levels of MITF. These data support p300 as a promising novel epigenetic therapeutic target in human melanoma.

ORGANISM(S): Homo sapiens

PROVIDER: GSE128737 | GEO | 2020/03/22

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:Dissection of melanoma heterogeneity through gene expression profiling has led to the identification of two major phenotypes, conventionally defined as “MITF high / proliferative” and “AXL high / invasive”. Tumors or single melanoma cells characterized by a predominant AXL-related gene program show enhanced expression of sets of genes involved in motility, invasion and regulation of epithelial-mesenchymal transition (EMT), while these genes are downregulated in tumors or cells with a predominant MITF-related gene program. The activation of the AXLhi/MITFlo invasive gene program in melanoma is characterized by aberrant expression of transcription factors (TFs) involved in the embryonic EMT process. Additional master genes involved in promoting melanoma growth and invasive state have been identified within the family of epigenetic regulators. Two of these genes, RNF2 and EZH2, components of the polycomb repressive complexes 1 and 2, act by epigenetically silencing tumor suppressors that in turn regulate the invasive and EMT-like phenotype of melanoma cells. Additional master genes involved in promoting melanoma growth and invasive state have been identified within the family of epigenetic regulators. Two of these genes, RNF2 and EZH2, components of the polycomb repressive complexes 1 and 2, act by epigenetically silencing tumor suppressors that in turn regulate the invasive and EMT-like phenotype of melanoma cells. Here we provide evidence for a new actionable pathway that controls melanoma EMT-like/invasive phenotype. We show that in MITFlo melanomas, the TF NFATc2 controls the EMT-like transcriptional program, the invasive ability of neoplastic cells, as well as in-vitro and in-vivo growth, through a pathway that functionally links c-myc to FOXM1 and EZH2. Targeting of NFATc2, FOXM1 or EZH2 inhibited melanoma migratory and invasive activity. Moreover, pharmacological co-targeting of NFATc2 and EZH2 promoted apoptosis of BRAF-mutant melanomas with intrinsic resistance to BRAF inhibition.

Dataset Information

MITF Expression Predicts Therapeutic Vulnerability to p300 Inhibition in Human Melanoma

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets