2. Academic Validation
  3. Bromodomain-containing protein 4 (BRD4) as an epigenetic regulator of fatty acid metabolism genes and ferroptosis

Bromodomain-containing protein 4 (BRD4) as an epigenetic regulator of fatty acid metabolism genes and ferroptosis

  • Cell Death Dis. 2022 Oct 29;13(10):912. doi: 10.1038/s41419-022-05344-0.
Minghua Yang # 1,  Ke Liu # 2,  Pan Chen 3,  Hongyi Zhu 4,  Junjie Wang 5,  Jun Huang 6
Affiliations

Affiliations

  • 1 Department of Pediatrics, The Third Xiangya Hospital, Central South University, Changsha, 410013, Hunan Province, P. R. China.
  • 2 Department of Ophthalmology, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan Province, P. R. China.
  • 3 Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan Province, P. R. China.
  • 4 Department of Gastroenterology, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan Province, P. R. China.
  • 5 Department of Orthopedics, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan Province, P. R. China.
  • 6 Department of Orthopedics, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan Province, P. R. China. 505447@csu.edu.cn.
  • # Contributed equally.
PMID: 36309482 DOI: 10.1038/s41419-022-05344-0
Abstract

Reprogramming lipid metabolism is considered a fundamental step in tumourigenesis that influences Ferroptosis. However, molecular mechanisms between lipid metabolism and Ferroptosis remain largely unknown. Results from the drug screening of 464 inhibitors (for 164 targets) applied to Ferroptosis cells indicated that 4 inhibitors targeted bromodomain-containing protein 4 (BRD4) significantly inhibiting erastin-induced Ferroptosis. Functional studies proved that the loss of BRD4 weakened oxidative catabolism in mitochondria, protecting cells from the excessive accumulation of lipid peroxides. Mechanism research revealed that the transcriptional levels of fatty acid metabolism-related genes (HADH, ACSL1 and ACAA2) participating in the β-oxidation of fatty acids (FAO) and polyunsaturated fatty acids (PUFAs) synthesis depended on the activity of super-enhancers (SEs) formed by BRD4 and HMGB2 in their promoter regions. Conclusively, this study demonstrated that BRD4 was indispensable for fatty acid metabolism based on its epigenetic regulatory mechanisms and affecting erastin-induced Ferroptosis, providing a new theoretical reference for understanding the relationship between lipid metabolism and Ferroptosis deeply.

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