Regulation of Ferroptosis by Transcription Factor E2F1 and RB

Abstract

Tumor suppressor RB binds to E2F family proteins and modulates cell cycle progression. Cyclin dependent kinases (CDK) regulate the interaction of RB/E2F by phosphorylating RB. Previously, we have revealed that CDK2, RB and E2F inhibit ferroptosis. Ferroptosis is a non-apoptotic, iron-dependent form of cell death characterized by toxic lipid peroxidation. Here we provide evidence that CDK2 suppresses ferroptosis through phosphorylation of RB. We approach this question by overexpressing WT-RB or a mutant RB that cannot be phosphorylated by CDKs (RBΔCDK) along with CDK2/cyclinE followed by analysis of ferroptosis. We also observed that E2F1 regulates of both pro and anti-ferroptotic proteins including ALOX5, MYC SLC7A11, ATF4, and GPX4 and finally renders a net inhibitory role in ferroptosis. Interestingly, we also found a cell type dependent compensatory effect of E2F3 upon E2F1 depletion. This compensatory effect resulted in no change of ferroptotic target genes after E2F1 knock down in an osteosarcoma cell line. Taken together, our study reveals that cancer cells protect themselves from ferroptosis through cell cycle regulatory proteins.

Targeting LxCxE cleft pocket of retinoblastoma protein in M2 macrophages inhibits ovarian cancer progression

“…3L ). This is not unexpected, given that AP-3-84 may target the Rb/E2F1 complex heavily involved in regulation of phospholipid metabolism, and PUFA-CL may undergo substantial oxidation leading to cell death (21,38). Similarly, PE, PC and PI species were sharply elevated mostly due to increased contents of PUFA-PE and PUFA- PC ( Supplementary Fig.…”

“…Specifically, LxCxE (Supplementary Fig. S1A) cleft pocket of Rb mediates interactions with numerous adaptor proteins able to mediate cell death outcomes such as E2F1, BAX, ASK1 and HDAC1 (16)(17)(18)(19)(20)(21). Due to previous data showing that the 1,2,4-thiadiazolidine-3,5-dione (TDZD)containing AP-3-84 compound (Supplementary Fig.…”

FSP1 is a predictive biomarker of osteosarcoma cells’ susceptibility to ferroptotic cell death and a potential therapeutic target

“…Interestingly, among other, we identi ed two potential consensus regions (responsive elements; RE) for the TFs E2F1 and p53, respectively (data not shown). We focused on these two TFs since p53 was previously suggested to potentially regulate FSP1 expression, and known to be involved in ferroptosis regulation, while E2F1, frequently deregulated in human osteosarcoma, has still an ambiguous role in ferroptosis regulation [36,37].…”