2. Academic Validation
  3. Menin-MLL1 complex cooperates with NF-Y to promote hepatocellular carcinoma survival

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

  • Cell Rep. 2025 Dec 23;44(12):116619. doi: 10.1016/j.celrep.2025.116619.
Margarita Dzama-Karels 1,  Mallory Sokolowski 1,  Peyton Kuhlers 1,  Jacqueline A Brinkman 1,  John P Morris 4th 2,  Jesse R Raab 3
Affiliations

Affiliations

  • 1 Department of Genetics, the University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • 2 Lineberger Comprehensive Cancer Center, the University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Pharmacology, the University of North Carolina at Chapel Hill Medical School, Chapel Hill, NC 27599, USA.
  • 3 Department of Genetics, the University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, the University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Electronic address: [email protected].
PMID: 41296561 DOI: 10.1016/j.celrep.2025.116619
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.

Keywords

CP: cancer; CP: molecular biology; CRISPR-Cas9 screen; HCC; NF-Y complex; liver cancer; menin inhibition; menin-MLL1 complex.

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