Menin-MLL complex cooperates with NF-Y to promote HCC survival [ATAC-seq]

Identification of new therapeutic targets in liver cancer remains critical. Chromatin regulating complexes are frequently mutated in liver cancer suggesting dysregulation of chromatin environments is a key feature driving liver cancer. We applied a focused CRISPR library targeting all genes involved in chromatin regulation to determine if the altered chromatin state of hepatocellular carcinoma cells could be targeted. The focused approach allowed us to test multiple cell lines in both 2D and 3D growth conditions which revealed striking differences in the essentiality of genes involved in ubiquitination and uncovered multiple chromatin regulators that are essential in 2D but whose loss promotes growth in 3D. We found the menin-MLL complex as among the strongest essential genes in all screens and deeply characterized the mechanism menin-MLL uses to promote hepatocellular carcinoma growth. Inhibition of menin-MLL led to global changes in occupancy of the complex and concomitant decreases in H3K4me3 and gene expression. A surprising increase in chromatin accessibility at sites not bound by menin-MLL was associated with recruitment of the pioneer transcription factor complex NF-Y. A screen of chromatin regulators in the presence of the menin-MLL inhibitor SNDX-5613 revealed a synergy between NF-YB loss and menin-MLL inhibition. Together these data show that menin-MLL is necessary for cell survival in HCC and cooperates with NF-Y to regulate transcription.