# Menin-MLL1 complex cooperates with NF-Y to promote hepatocellular carcinoma survival

## TL;DR

This study shows that the menin-MLL1 complex is essential for liver cancer cell survival and works with NF-Y to control gene activity.

## Contribution

The study reveals a novel cooperative mechanism between menin-MLL1 and NF-Y in promoting hepatocellular carcinoma survival.

## Key findings

- Menin-MLL1 complex disruption reduces H3K4me3 and gene expression in liver cancer cells.
- NF-Y recruitment to newly opened chromatin sites suggests priming for gene expression.
- Combining menin inhibition with NFYB knockout significantly increases cancer cell death.

## Abstract

Chromatin regulators are frequently mutated or aberrantly expressed in hepatocellular carcinoma (HCC), suggesting that the dysregulation of chromatin is a key feature driving liver cancer. In this study, using an epigenome-focused CRISPR screen in two-dimensional (2D) and three-dimensional (3D) conditions, we find the subunits of the menin-MLL1 complex to be among the strongest candidates for HCC survival. Inhibition of the menin-MLL1 interaction leads to global changes in occupancy of the complex with concomitant decreases in H3 lysine 4 trimethylation (H3K4me3), accessibility, and gene expression. Newly opened chromatin sites not bound by menin-MLL1 are associated with the recruitment of the pioneer transcription factor complex NF-Y yet remain embedded in silent chromatin domains, suggesting that they are primed for expression. A CRISPR-Cas9 screen of chromatin regulators in the presence of menin inhibitor SNDX-5613 reveals a significantly increased cell death when combined with NFYB knockout. Together, these data show that menin-MLL1 is necessary for HCC cell survival and cooperates with NF-Y to regulate oncogenic gene transcription.

Dzama-Karels et al. identify the menin-MLL1 complex as crucial for hepatocellular carcinoma survival. Its disruption disturbs the PI3k/AKT/mTOR signaling pathway and chromatin accessibility. Menin inhibition promotes the redistribution of the NF-Y complex to sites associated with cell migration and invasion. Combining menin inhibition and NFYB knockout increases hepatocellular carcinoma cell death.