Homeostasis Imbalance of YY2 and YY1 Promotes Tumor Growth by Manipulating Ferroptosis

Abstract

Ferroptosis is a type of programmed cell death caused by disruption of redox homeostasis and is closely linked to amino acid metabolism. Yin Yang 2 (YY2) and its homolog Yin Yang 1 (YY1) are highly homologous, especially in their zinc-finger domains. Furthermore, they share a consensus DNA binding motif. Increasing evidences have demonstrated the tumor suppressive effect of YY2, in contrast with the oncogenic YY1; however, little is known about the biological and pathological functions of YY2. Here, it is determined that YY2 induces tumor cell ferroptosis and subsequently suppresses tumorigenesis by inhibiting solute carrier family 7 member 11 (SLC7A11) transcription, leading to the decreased glutathione biosynthesis. Furthermore, YY2 and YY1 bind competitively to the same DNA binding site in the SLC7A11 promoter and antagonistically regulate tumor cell ferroptosis, thus suggesting the molecular mechanism underlying their opposite regulation on tumorigenesis. Moreover, mutations of YY2 zinc-finger domains in clinical cancer patients abrogate YY2/SLC7A11 axis and tumor cell ferroptosis. Together, these results provide a new insight regarding the regulatory mechanism of ferroptosis, and a mechanistic explanation regarding the tumor suppressive effect of YY2. Finally, these findings demonstrate that homeostasis between YY1 and YY2 is crucial for maintaining redox homeostasis in tumor cells.

Loss of LncRNA DUXAP8 synergistically enhanced sorafenib induced ferroptosis in hepatocellular carcinoma via SLC7A11 de‐palmitoylation

“…Ferroptosis modulates the pathogenesis and the progression of HCC. For example, metallothionein‐1G, 15 the p62/NRF2 pathway, 26 and the S47 variant of the TP53 gene 37 all protect against ferroptosis and hepatocarcinogenesis 38–40 . However, the regulation of SLC7A11 and cell ferroptosis by lncRNA remains largely uncharacterized.…”

The Regulatory Role of Ferroptosis in Bone Homeostasis

“…Furthermore, GPX4 is considered a crucial molecule in the regulation of ferroptosis [ 24 ]. The basis of ferroptosis is the presence of free iron in the cells.…”

“…Furthermore, GPX4 is considered a crucial molecule in the regulation of ferroptosis [24]. The basis of ferroptosis is RCD: regulated cell death; PTGS2: prostaglandin endoperoxide synthase 2; FSP1: fibroblast-specific protein 1; NRF2: nuclear factor erythroid 2-related factor 2; DFO: desferrioxamine.…”

Crosstalk between regulated necrosis and micronutrition, bridged by reactive oxygen species

“…Yin Yang 2 (YY2) protein manipulated cellular redox homeostasis, which induced tumor cell ferroptosis and suppressed tumorigenesis. Mechanistically, YY2 competed against its homolog YY1 to bind SLC7A11 promoter, which blocked transcription of SLC7A11 and associated GSH biosynthesis (182). Mutation of YY2 zincfinger domains disturbed the interaction between YY2 and SLC7A11, and abrogated ferroptosis (182).…”

“…Mechanistically, YY2 competed against its homolog YY1 to bind SLC7A11 promoter, which blocked transcription of SLC7A11 and associated GSH biosynthesis (182). Mutation of YY2 zincfinger domains disturbed the interaction between YY2 and SLC7A11, and abrogated ferroptosis (182). A20 was identified that directly interacted with ACSL4, whose upregulation promoted erastin-induced ferroptosis in endothelial cells (183).…”