# Gene Amplification of Mediator Subunit 30 Redirects the MYC Transcriptional Program and Oncogenesis

## TL;DR

This study shows how overexpression of MED30 changes MYC's activity in cancer, leading to worse outcomes and suggesting MED30 as a potential treatment target.

## Contribution

The study reveals a novel mechanism where MED30 overexpression redirects MYC's transcriptional program in cancer.

## Key findings

- MED30 overexpression leads MYC to a new transcriptional program linked to poor prognosis.
- MED30 recruits Mediator components and MYC to new genomic sites, creating enhancers for cancer progression.
- MED30 overexpression promotes tumor growth in PDAC and GBM, which can be reduced by MYC knockdown.

## Abstract

Understanding the molecular mechanisms underlying tumorigenesis is crucial for developing effective cancer therapies. Here, we investigate the 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 as an example, MED30 knockdown reduces tumor growth particularly in MYC high-expressed glioblastoma (GBM) cell lines. Overall, our study elucidates the critical role of MED30 overexpression in orchestrating oncogenic transcriptional programs and highlights its potential as a therapeutic target for MYC-amplified cancer.