Modulation of the p38 MAPK Pathway by Anisomycin Promotes Ferroptosis of Hepatocellular Carcinoma through Phosphorylation of H3S10

Abstract

Hepatocellular carcinoma (HCC) is a prevalent malignant tumor worldwide. Ferroptosis is emerging as an effective target for tumor treatment as it has been shown to potentiate cell death in some malignancies. However, it remains unclear whether histone phosphorylation events, an epigenetic mechanism that regulates transcriptional expression, are involved in ferroptosis. Our study found that supplementation with anisomycin, an agonist of p38 mitogen-activated protein kinase (MAPK), induced ferroptosis in HCC cells, and the phosphorylation of histone H3 on serine 10 (p-H3S10) was participated in anisomycin-induced ferroptosis. To investigate the anticancer effects of anisomycin-activated p38 MAPK in HCC, we analyzed cell viability, colony formation, cell death, and cell migration in Hep3B and HCCLM3 cells. The results showed that anisomycin could significantly suppress HCC cell colony formation and migration and induce HCC cell death. The hallmarks of ferroptosis, such as abnormal accumulation of iron and elevated levels of lipid peroxidation and malondialdehyde, were detected to confirm the ability of anisomycin to promote ferroptosis. Furthermore, coincubation with SB203580, an inhibitor of activated p38 MAPK, partially rescued anisomycin-induced ferroptosis. And the levels of p-p38 MAPK and p-H3S10 were successively increased by anisomycin treatment. The relationship between p-H3S10 and ferroptosis was revealed by ChIP sequencing. The reverse transcription PCR and immunofluorescence results showed that NCOA4 was upregulated both in mRNA and protein levels after anisomycin treatment. And by C11-BODIPY staining, we found that anisomycin-induced lipid reactive oxygen species was reduced after NCOA4 knockdown. In conclusion, the anisomycin-activated p38 MAPK promoted ferroptosis of HCC cells through H3S10 phosphorylation.

Autophagy mediates an amplification loop during ferroptosis

“…In contrast, some additional studies explained the pathways and mechanisms accounting for ROS-initiated autophagy during ferroptosis [ 11 , 20 , 95 ]. A study investigated the role of ROS in regulating autophagy during ferroptosis [ 20 ].…”

Targeting epigenetic and posttranslational modifications regulating ferroptosis for the treatment of diseases

“… 536 HCC Anisomycin Phosphorylation p38MAPK Anisomycin activates p38MAPK to induce ferritinophagy through the phosphorylation of histone H3 on serine 10 (p-H3S10). 537 NSCLC Bufotalin Ubiquitination GPX4 Bufotalin induces ferroptosis by facilitating the ubiquitination and degradation of GPX4. 538 NSCLC Sanguinarine Ubiquitination GPX4 Sanguinarine triggered ferroptosis through decreasing the protein stability of GPX4 through E3 ligase STUB1-mediated ubiquitination and degradation of endogenous GPX4.…”

“… 536 Anisomycin activates p38MAPK to induce ferritinophagy through the phosphorylation of histone H3 on serine 10 (p-H3S10) in HCC. 537 …”

Ferroptosis: Potential opportunities for natural products in cancer therapy

“…Nitidine chloride inhibited the phosphatidylinositol 3‐kinase (PI3K)/protein kinase B (AKT) pathway by promoting the degradation of ATP‐binding cassette subfamily B member 6 (ABCB6), thereby triggering the execution of ferroptosis in multiple myeloma cells (Yin et al, 2023). Furthermore, anisomycin promoted the phosphorylation of histone H3 on Ser 10 (H3S10) by activating p38 mitogen‐activated protein kinase (MAPK), which resulted in increased levels of free iron, lipid peroxide, and MDA in HCC cells via up‐regulating NCOA4 (W. Chen et al, 2022). These findings imply that anisomycin inhibits HCC progression through enhancing ferroptosis.…”