Transcriptional Repression of Ferritin Light Chain Increases Ferroptosis Sensitivity in Lung Adenocarcinoma

Abstract

Ferroptosis is an iron- and lipid peroxidation-dependent form of regulated cell death. The release of labile iron is one of the important factors affecting sensitivity to ferroptosis. Yes-associated protein (YAP) controls intracellular iron levels by affecting the transcription of ferritin heavy chain (FTH) and transferrin receptor (TFRC). However, whether YAP regulates iron metabolism through other target genes remains unknown. Here, we observed that the system Xc– inhibitor erastin inhibited the binding of the WW domain and PSY motif between YAP and transcription factor CP2 (TFCP2), and then suppressed the transcription of ferritin light chain (FTL) simultaneously mediated by YAP, TFCP2 and forkhead box A1 (FOXA1). Furthermore, inhibition of FTL expression abrogated ferroptosis-resistance in cells with sustained YAP expression. Unlike FTH, which exhibited first an increase and then a decrease in transcription, FTL transcription continued to decline after the addition of erastin, and a decrease in lysine acetyltransferase 5 (KAT5)-dependent acetylation of FTL was also observed. In lung adenocarcinoma (LUAD) tissues, lipid peroxidation and labile iron decreased, while YAP, TFCP2 and FTL increased compared to their adjacent normal tissues, and the lipid peroxidation marker 4-hydroxynonenal (4-HNE) was negatively correlated with the level of FTL or the degree of LUAD malignancy, but LUAD tissues with lower levels of 4-HNE showed a higher sensitivity to ferroptosis. In conclusion, the findings from this study indicated that the suppression of FTL transcription through the inhibition of the YAP-TFCP2-KAT5 complex could be another mechanism for elevating ferroptosis sensitivity and inducing cell death, and ferroptotic therapy is more likely to achieve better results in LUAD patients with a lower degree of lipid peroxidation.

Integrated Analysis Reveals Critical Ferroptosis Regulators and FTL Contribute to Cancer Progression in Hepatocellular Carcinoma

“…Gsk-3β affects ferroptosis by antagonizing iron metabolites, including FTL, and disrupting iron homeostasis ( Wang et al, 2021a ). Transcriptional inhibition of FTL has also been reported to increase the sensitivity of cancer cells to ferroptosis in lung adenocarcinoma ( Wang et al, 2021b ). In this study, we found that the level of FTL expression was also associated with immunotherapy and molecular targeted therapy, including sorafenib and imatinib.…”

Iron Administration Overcomes Resistance to Erastin-Mediated Ferroptosis in Ovarian Cancer Cells

“…One can be found in the molecular mechanisms regulating intracellular iron homeostasis: in COV318 cells the increase of intracellular free iron, secondary to ferritinophagy, may engage the IRE/IRP machinery leading to the upregulation of ferritin synthesis as a mechanism of cell self-protection ( 55 ). Alternatively, erastin may promote FtH transcription through the activation of the transcriptional factor Nrf-2 or through the downregulation of YAP pathway as very recently demonstrated in hepatocellular carcinoma and lung adenocarcinoma, respectively ( 13 , 56 ). Which of the aforementioned or some yet-unknown mechanisms are involved in the restriction of ferroptosis in COV318 will be deepened in a future work.…”

YAP1 alleviates sepsis-induced acute lung injury via inhibiting ferritinophagy-mediated ferroptosis

“…In doxorubicin-induced myocardial damage models, YAP could decrease the expression level of ACSL4 ( 22 ). In lung adenocarcinoma, YAP diminished intracellular iron levels by promoting FTL transcription through transcription factor CP2 (TRCP2) ( 39 ). To clarify the mechanism of ferroptosis in sepsis-induced ALI, a transcriptome study of RNA sequencing was carried out, suggesting that the ferroptosis signaling pathway was involved in the pathogenesis of sepsis-induced ALI.…”