Accéder au contenu
Merck

A CRISPR-Cas9 library screening identifies CARM1 as a critical inhibitor of ferroptosis in hepatocellular carcinoma cells.

Molecular therapy. Nucleic acids (2023-11-29)
Yiming Cheng, Xiaochen Wang, Shuyu Huang, Liang Zhang, Bei Lan, Xuanyuan Li, Hao Chen, Zhenfeng Liu, Yijie Su, Lishan Xi, Shengyun Feng, Yanxuan Guo, Jun Zhou, Yingmei Wang, Chenghao Xuan
RÉSUMÉ

Ferroptosis is an iron-catalyzed form of regulated cell death that results from the accumulation of lipid peroxidation products and reactive oxygen species to a lethal content. However, the transcriptional regulation of ferroptosis is not well understood. Sorafenib, a standard drug for hepatocellular carcinoma (HCC), induces ferroptosis in HCC cells. In this study, we conducted a CRISPR-Cas9 library screening targeting epigenetic factors and identified coactivator-associated arginine methyltransferase 1 (CARM1) as a critical inhibitor of ferroptosis. CARM1 depletion intensified Sorafenib-induced ferroptosis, resulting in decreased cell viability, reduced cellular glutathione level, increased lipid peroxidation, and altered mitochondrial crista structure. Additionally, we investigated a CARM1 inhibitor (CARM1i) as a potential ferroptosis inducer. Combining the CARM1i with Sorafenib enhanced the induction of ferroptosis. Notably, both CARM1 knockdown and CARM1i showed cooperative effects with Sorafenib in inhibiting HCC growth in mice. The underlying mechanism involves CARM1-catalyzed H3R26me2a on the promoter of glutathione peroxidase 4, leading to its transcriptional activation and subsequent ferroptosis inhibition. Furthermore, Sorafenib treatment induced the transcription of CARM1 through the MDM2-p53 axis. In summary, our findings establish CARM1 as a critical ferroptosis inhibitor and highlight the potential of CARM1is as novel ferroptosis inducers, providing promising therapeutic strategies for HCC treatment.

MATÉRIAUX
Référence du produit
Marque
Description du produit

Sigma-Aldrich
Anticorps monoclonal ANTI-FLAG® M2 antibody produced in mouse, clone M2, purified immunoglobulin (Purified IgG1 subclass), buffered aqueous solution (10 mM sodium phosphate, 150 mM NaCl, pH 7.4, containing 0.02% sodium azide)
Sigma-Aldrich
Bafilomycin A1, Streptomyces griseus, Bafilomycin A1, CAS 88899-55-2, acts as a highly potent and specific inhibitor of vacuolar-type H+-ATPase (Ki = 500 pM). Blocks the fusion of autophagosome with lysosome.
Sigma-Aldrich
CARM1 Inhibitor, The CARM1 Inhibitor controls the biological activity of CARM1. This small molecule/inhibitor is primarily used for Cell Structure applications.