2. Academic Validation
  3. EP300 promotes ferroptosis via HSPA5 acetylation in pancreatic cancer

EP300 promotes ferroptosis via HSPA5 acetylation in pancreatic cancer

  • Sci Rep. 2023 Sep 11;13(1):15004. doi: 10.1038/s41598-023-42136-8.
Yuan Wang 1 2,  Yang Liu 1 2,  Cong Wang 1 2,  Rui Kang 3,  Daolin Tang 4,  Jiao Liu 5 6
Affiliations

Affiliations

  • 1 DAMP Laboratory, Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510150, Guangdong, China.
  • 2 Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, Guangzhou Medical University, Guangzhou, 510150, Guangdong, China.
  • 3 Department of Surgery, UT Southwestern Medical Center, Dallas, TX, 75390, USA.
  • 4 Department of Surgery, UT Southwestern Medical Center, Dallas, TX, 75390, USA. [email protected].
  • 5 DAMP Laboratory, Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510150, Guangdong, China. [email protected].
  • 6 Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, Guangzhou Medical University, Guangzhou, 510150, Guangdong, China. [email protected].
PMID: 37696842 DOI: 10.1038/s41598-023-42136-8
Abstract

Ferroptosis is a form of regulated cell death characterized by oxidative injury-induced lipid peroxidation. However, the detailed protein post-translational modification regulatory mechanism of Ferroptosis remains largely unknown. Here, we report that E1A binding protein P300 (EP300) acetyltransferase promotes Ferroptosis in human pancreatic ductal adenocarcinoma (PDAC) cells via the acetylation of heat shock protein family A (HSP70) member 5 (HSPA5), also known as GRP78 or BIP) on the site of K353. Acetylated HSPA5 loses its ability to inhibit lipid peroxidation and subsequent ferroptotic cell death. Genetic or pharmacological inhibition of EP300-mediated HSPA5 acetylation on K353 increases PDAC cell resistance to Ferroptosis. Moreover, histone deacetylase 6 (HDAC6) limits HSPA5 acetylation and subsequent Ferroptosis. Collectively, these findings not only identify regulatory pathways for HSPA5 acetylation during Ferroptosis, but also highlight promising strategies to increase Ferroptosis sensitivity in PDAC cells.

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