Gene Amplification of Mediator Subunit 30 Redirects the MYC Transcriptional Program and Oncogenesis [Pro-Seq]

Understanding the molecular mechanisms underlying tumorigenesis is crucial for developing effective cancer therapies. Here, we investigate the common co-amplification of MED30 and MYC across diverse cancer types and its impact on oncogenic transcriptional programs. Transcriptional profiling of MYC and MED30 single or both overexpression/amplification revealed the over amount of MED30 lead MYC to a new transcriptional program that associate with poor prognosis. Mechanistically, MED30 overexpression/amplification recruits other Mediator components and binding of MYC to a small subset of novel genomic regulatory sites, changing the epigenetic marks and inducing the formation of new enhancers, which drive the expression of target genes crucial for cancer progression. In vivo studies in pancreatic ductal adenocarcinoma (PDAC) further validate the oncogenic potential of MED30, as its overexpression promotes tumor growth and can be attenuated by knockdown of MYC. Using another cancer type, MED30 knockdown reduces tumor growth particularly in MYC high-expressed glioblastoma (GBM) cell lines. Overall, our study elucidates the critical role of MED30 overexprssion in orchestrating oncogenic transcriptional programs and highlights its potential as a therapeutic target for MYC-amplified cancer. Transcriptional activity was measured by PRO-seq in doxycycline (Dox) inducible MED30, MYC-3xHA or MED30&MYC-3xHA double integrated Mia PaCa-2 cell line with or without 0.5μg/ml Dox treatment for 1 day. Samples with Dox treatment were labeled as OE (overexpression). Processed files are feature counts per gene.