# E2F1 K117 methylation by SETD6 disrupts BRD4–E2F1 binding and modulates E2F1 chromatin binding and gene regulation in prostate cancer cells

## TL;DR

This study shows how SETD6 modifies E2F1 in prostate cancer cells, affecting gene regulation and cancer-related behaviors.

## Contribution

The study reveals a novel mechanism where SETD6 methylation of E2F1 disrupts its interaction with BRD4, modulating gene regulation.

## Key findings

- Methylated and unmethylated E2F1 bind and upregulate distinct sets of genes.
- SETD6-mediated K117 methylation prevents E2F1 acetylation and disrupts BRD4 binding.
- E2F1 methylation influences oncogenic phenotypes in prostate cancer cells.

## Abstract

The SETD6 (SET domain-containing protein 6) protein lysine methyltransferase regulates various cellular processes including cancer initiation and progression. It monomethylates the transcription factor E2F1 (E2F transcription factor 1) and several other important proteins, but the functional consequences of many SETD6 mediated methylation events are unknown. In this study, the role of SETD6 mediated K117 monomethylation of E2F1 was investigated in prostate cancer cells. In chromatin binding and gene expression experiments, we identified distinct sets of genes that are bound and upregulated by methylated and unmethylated E2F1 indicating that E2F1 methylation by SETD6 directly modulates its chromatin interaction. In agreement with these findings, cellular data showed that E2F1 methylation affects oncogenic phenotypes. Mechanistically, we demonstrate with biochemical, cellular, and genomic assays that SETD6-mediated K117 methylation directly regulates the interaction of E2F1 and BRD4 by preventing K117 acetylation. Our data suggest that K117 methylation/acetylation represents a switch controlling bromodomain binding to E2F1 by which SETD6 methylation regulates different cellular effects of E2F1. Similar mechanisms may apply to the regulation of other transcription factors by SETD6.

Graphical Abstract