Related Experiment Video
Updated: May 10, 2025
00:06
An Oncogenic Hepatocyte-Induced Orthotopic Mouse Model of Hepatocellular Cancer Arising in the Setting of Hepatic Inflammation and Fibrosis
Published on: September 12, 2019
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Menin-MLL1 complex cooperates with NF-Y to promote HCC survival
Margarita Dzama-Karels1, Peyton Kuhlers1, Mallory Sokolowski1
1Department of Genetics, The University of North Carolina at Chapel Hill, Chapel Hill NC, USA.
Biorxiv : the Preprint Server for Biology
|April 28, 2025
Summary
Targeting the menin-MLL1 complex is crucial for hepatocellular carcinoma (HCC) treatment. This complex, along with NF-Y, drives liver cancer growth by regulating oncogenic gene transcription.
Area of Science:
- Oncology
- Epigenetics
- Molecular Biology
Background:
- Hepatocellular carcinoma (HCC) requires new therapeutic targets.
- Dysregulation of chromatin environments is a key driver of liver cancer.
- Chromatin regulators are frequently mutated or aberrantly expressed in HCC.
Purpose of the Study:
- To investigate targeting altered chromatin states in HCC cells.
- To identify essential chromatin regulators for HCC survival.
- To elucidate the mechanism of menin-MLL1 complex in HCC progression.
Main Methods:
- Utilized an epigenome-focused CRISPR library targeting chromatin regulators.
- Screened multiple HCC cell lines in 2D and 3D culture conditions.
- Investigated menin-MLL1 complex inhibition effects on gene expression and chromatin accessibility.
Main Results:
- Found menin-MLL1 complex subunits essential for HCC cell survival in all screens.
- Demonstrated menin-MLL1 inhibition decreases H3K4me3 and PI3K/AKT/mTOR signaling.
- Showed menin inhibition increases chromatin accessibility, recruiting NF-Y.
- Identified combined menin inhibition and NFYB knockout significantly increases cell death.
Conclusions:
- The menin-MLL1 complex is essential for HCC cell survival.
- Menin-MLL1 cooperates with NF-Y to regulate oncogenic transcription in HCC.
- Targeting the menin-MLL1 complex presents a promising therapeutic strategy for HCC.
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