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 smallmolecule inhibition of p300 HAT activity.

<p>CCNB1 Expedites the Progression of Cervical Squamous Cell Carcinoma via the Regulation by FOXM1</p>

“…Kim et al proposed that suppression of p300 acetyltransferase activity with the help of a catalytic p300/CBP inhibitor exhibited effective growth inhibitory effects in melanoma cells. 26 Functional rescue experiments in our study further validated that the CBP/P300-specific activator CTPB promoted EdU-positive cells and reduced apoptosis in the presence of siCCNB1. Lastly, GSEA in the present study disclosed that p53 pathway was significantly conversely regulated in CSCC.…”

Inherited variations in human pigmentation-related genes modulate cutaneous melanoma risk and clinicopathological features in Brazilian population

“…Previous studies showed that increased ADCY expression generated resistance to MAPK inhibitions and up regulates MITF in melanoma cells 8 , and the suppression of MITF expression by the CH6868398 agent caused melanoma cell growth inhibition 45 . Inhibition of p300 acetyltransferase transcriptional coactivator of MITF by p300/CBP complex had growth inhibitory effects in melanoma cells expressing MITF 46 , 47 , and Kazinol U reduced melanogenesis by inhibition of MITF in melanoma cells 48 . Since response to new agents depends on ADCY3 and MITF expressions, it is possible that patients with distinct genotypes of these genes present differentiated responses to therapies.…”

Unraveling the chaotic genomic landscape of primary and metastatic canine appendicular osteosarcoma with current sequencing technologies and bioinformatic approaches

“…In this study both dogs had MITF amplification and the Sheepdog had a CDKN2A deletion and a BRAF amplification and thus considered as a potential driver in this study. MITF activity has been linked to acquired resistance to MAPK inhibitors [ 92 ] and thus it is predicted that MAPK inhibitors will be ineffective in tumors with MITF amplification. MITF is a downstream target of EP300 , a histone acetyltransferase and an oncogene in a subset of melanomas.…”

“…There are no current MITF targeted therapies. Instead EP300 targeted therapy have shown potential in preclinical models of MITF overexpressing melanomas [ 92 ]. EP300 therapy may have been effective in the metastatic lesion of the Sheepdog with MITF and EP300 amplification.…”