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EP300 promotes ferroptosis via HSPA5 acetylation in pancreatic cancer

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.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Yuan Wang

LAB HEAD: Jiao Liu

PROVIDER: PXD039998 | Pride | 2023-10-24

REPOSITORIES: Pride

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EP300 promotes ferroptosis via HSPA5 acetylation in pancreatic cancer.

Wang Yuan Y Liu Yang Y Wang Cong C Kang Rui R Tang Daolin D Liu Jiao J

Scientific reports 20230911 1

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 K ...[more]

PMID: 37696842

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Project description:Ferroptosis is a form of regulated cell death driven by lipid peroxidation of polyunsaturated fatty acids (PUFAs). Endogenous PUFAs are nonconjugated PUFAs and their peroxidation proceeds via the hydrogen-atom transfer (HAT) mechanism. We previously reported that lipids with conjugated double bonds undergo lipid peroxidation mostly via a different mechanism, peroxyl radical addition (PRA), and were much more readily oxidizable than nonconjugated ones. In this study, we aim to elucidate the effects of various unsaturated lipids in sensitizing ferroptosis. We found that while some peroxidation-reactive lipids, such as 7-dehydrocholesterol, vitamins D3 and A, and coenzyme Q10, suppress ferroptosis, both nonconjugated and conjugated PUFAs enhanced cell death induced by RSL3, a ferroptosis inducer. Importantly, we showed that conjugated linolenic acid (CLA 18:3) could act as a ferroptosis inducer by itself and conjugated linoleic acid (CLA 18:2) was more potent in sensitizing cells to RSL3-induced cell death than any nonconjugated PUFAs. We next sought to elucidate the mechanism underlying the different ferroptosis-inducing potency of conjugated and nonconjugated PUFAs. Lipidomics revealed that conjugated and nonconjugated PUFAs are incorporated into distinct cellular lipid species. Furthermore, the different peroxidation mechanisms predict the formation of higher levels of reactive electrophilic aldehydes from conjugated PUFAs than nonconjugated PUFAs, which was confirmed by aldehyde-trapping and mass spectrometry. RNA sequencing revealed that protein processing in the endoplasmic reticulum and proteasome are among the most significantly upregulated pathways in cells treated with CLA 18:3, suggesting increased ER stress and activation of unfolded protein response. Significantly, using click chemistry, we observed increased protein adduction by oxidized lipids in cells treated with an alkynylated CLA 18:2 probe. These results suggest that protein damage by lipid electrophiles is a key step in ferroptosis.

Project description:Pancreatic ductal adenocarcinoma (PDAC) is one of the most intractable malignancies and systematic chemotherapies are the most commonly-used standard treatment for PDAC patients diagonosed at advanced stages. However, drug resistance may arise as early as several weeks after chemotherapy initiation, thus limiting the therapeutic efficacy of chemotherapy reagents. Accumulating evidence has demonstrated that acquired tolerance to apoptotic cell death induced by cytotoxic drugs is one of the critical reasons for the failure of chemotherapy. Ferroptosis was originally identified as a unique form of programmed cell death, which is characterized by shrunk mitochondria accompanied with condensed membranes and decreased crista, in drug screens searching for small molecules that can selectively kill RAS-expressing cancer cells. Unlike apoptosis, ferroptosis is driven by iron-catalyzed excessive lipid peroxidation, ultimately leading to the rupture of plasma membrane and cell death. Recent studies indicated that ferroptosis induction can be a promising therapeutic strategy in cancer treatment since it not only can kill tumor cells directly but also can synergize with chemotherapy ,radiotherapy,targeted therapy and immunotherapy. However, transformed malignant cells can acquired resistance to ferroptosis through adaptative changes in their epigenome, genome, transcriptome, translatome or proteome. Multiple mechanisms, such as decreased coenzyme Q10 production mediated by the upregulation of apoptosis-inducing factor mitochondria-associated 2 (AIFM2/FSP1) and elevated expression of cytoprotective genes as a result of the activation of antioxidant transcription factor NFE2L2/NRF2 (nuclear factor erythroid 2-like 2), have been demonstrated to confer ferroptosis resistance. However, transformed malignant cells can acquired resistance to ferroptosis through adaptative changes in their epigenome, genome, transcriptome, translatome or proteome. Multiple mechanisms, such as decreased coenzyme Q10 production mediated by the upregulation of apoptosis-inducing factor mitochondria-associated 2 (AIFM2/FSP1) and elevated expression of cytoprotective genes as a result of the activation of antioxidant transcription factor NFE2L2/NRF2 (nuclear factor erythroid 2-like 2), have been demonstrated to confer ferroptosis resistance. Therefore, unravelling the underlying mechanisms responsible for reduced sensitivity to ferroptosis inducers, such as erastin or RSL3, may pave the way for designing effective therapeutic regimens for PDAC patients.

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