SOCS1 regulates senescence and ferroptosis by modulating the expression of p53 target genes

Abstract

The mechanism by which p53 suppresses tumorigenesis remains poorly understood. In the context of aberrant activation of the JAK/STAT5 pathway, SOCS1 is required for p53 activation and the regulation of cellular senescence. In order to identify p53 target genes acting during the senescence response to oncogenic STAT5A, we characterized the transcriptome of STAT5A-expressing cells after SOCS1 inhibition. We identified a set of SOCS1-dependent p53 target genes that include several secreted proteins and genes regulating oxidative metabolism and ferroptosis. Exogenous SOCS1 was sufficient to regulate the expression of p53 target genes and sensitized cells to ferroptosis. This effect correlated with the ability of SOCS1 to reduce the expression of the cystine transporter SLC7A11 and the levels of glutathione. SOCS1 and SOCS1-dependent p53 target genes were induced during the senescence response to oncogenic STAT5A, RasV12 or the tumor suppressor PML. However, while SOCS1 sensitized cells to ferroptosis neither RasV12 nor STAT5A mimicked the effect. Intriguingly, PML turned cells highly resistant to ferroptosis. The results indicate different susceptibilities to ferroptosis in senescent cells depending on the trigger and suggest the possibility of killing senescent cells by inhibiting pathways that mediate ferroptosis resistance.

The tumor suppressor protein p53 and the ferroptosis network

“…The bidirectional control of ferroptosis by p53 through transcription-dependent and -independent mechanisms is context-dependent [11][12][13][14]. Furthermore, p53 is a multifunctional protein with multiple potential modifications and biochemical properties from the regulation by single-nucleotide polymorphism, long non-coding RNAs, and SOCS1 (suppressor of cytokine signaling 1) in ferroptosis [82][83][84][85][86].…”

Nrf2 and Ferroptosis: A New Research Direction for Neurodegenerative Diseases

“…The histone deubiquitinating enzyme breast cancer 1(BRCA1)-associated protein 1 (BAP1) also inhibits SLC7A11 by reducing H2A ubiquitination (H2Aub) on the SLC7A11 promoter . Cytokine signaling 1 (SOCS1) is required for p53 activation and the regulation of cellular senescence, and SOCS1 is sufficient to regulate the expression of p53 target genes and sensitized cells to ferroptosis by reducing the expression of the cystine transporter SLC7A11 and the levels of GSH (Saint-Germain et al, 2017). Histone H2B on lysine 120 (H2Bub1) is an epigenetic mark generally associated with transcriptional activation, and H2Bub1 epigenetically activates the expression of SLC7A11, but p53 decreases H2Bub1 occupancy on the SLC7A11 gene regulatory region and represses the expression of SLC7A11 during ferroptosis process (Wang et al, 2019f).…”

Targeted p53 on Small-Molecules-Induced Ferroptosis in Cancers

“…Aside from influencing p53 target gene expression, SOCS1 also plays a general role in senescence by stabilizing the interactions of p53 with protein complexes at DNA damage foci (Figure 2 ). This function of SOCS1 allows the maintenance of a pool of preactive p53 that could be slowly released and contribute to generate a lasting chronic p53 response ( 67 ). SOCS1 activates the functions of p53 via facilitating the serine 15 phosphorylation of p53 and stabilizing p53 by interfering with KAP1 ( 67 ).…”