Abstract 1697: Phase separation of BHLHE40 up-regulates SREBF1 and inhibits ferroptosis in pancreatic cancer cells

Abstract

Abstract Pancreatic cancer (PCa) is one of the most lethal malignancies in human cancers. The enhanced infiltration of stromal tissue of PCa tumor microenvironment limits the identification of key tumor-specific transcription factors and epigenomic abnormalities in malignant epithelial cells. Integrated transcriptome and epigenetic multi-omics analysis of paired PCa organoids indicated that the basic helix-loop-helix transcription factor 40 (BHLHE40) was significantly upregulated in tumor samples. Increased chromatin accessibility at promoter region and enhanced mTOR pathway activity contribute to the elevated expression of BHLHE40. Integrated analysis of chromatin immunoprecipitation (ChIP)-seq, RNA-seq and high-through chromosome conformation capture (Hi-C) data together with chromosome conformation capture (3C) assay indicate that BHLHE40 not only regulates the sterol regulatory element-binding factor 1 (SREBF1) transcription as a classic transcription factor, but also links the enhancer and promoter regions of SREBF1 via forming liquid-liquid phase-separated droplets. Then, we find the BHLHE40-SREBF1-stearoyl-CoA desaturase (SCD1) axis protects PCa cells from ferroptosis, leading to the reduced accumulation of lipid peroxidation in cells. Moreover, SREBF1 inhibitor, Fatostatin, significantly suppresses the cell growth of PCa tumors with higher expression of BHLHE40. This study highlights the important roles of BHLHE40 mediated lipid peroxidation in inducing ferroptosis of PCa cells and provides a novel mechanism underlying the SREBF1 overexpression in PCa. Citation Format: Yizhi Cao, Xuelong Wang, Yang Liu, Pengyi Liu, Jiejie Qin, Youwei Zhu, Shuyu Zhai, Minmin Shi, Weishen Wang, Xiaxing Deng, Chenghong Peng, Hao Chen, Ruibao Ren, Lingxi Jiang, Baiyong Shen. Phase separation of BHLHE40 up-regulates SREBF1 and inhibits ferroptosis in pancreatic cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1697.