SOCS3-mediated activation of p53-p21-NRF2 axis and cellular adaptation to oxidative stress in SOCS1-deficient hepatocellular carcinoma

Abstract

SOCS1 and SOCS3 genes, frequently repressed in hepatocellular carcinoma (HCC), function as tumor suppressors in hepatocytes. However, TCGA transcriptomic data revealed that SOCS1-low/SOCS3-high specimens displayed more aggressive HCC than SOCS1-low/SOCS3-low cases. We show that hepatocyte-specific Socs1-deficient livers upregulate Socs3 expression following genotoxic stress. Whereas deletion of Socs1 or Socs3 increased HCC susceptibility, ablation of both genes attenuated HCC growth. SOCS3 promotes p53 activation in SOCS1-deficient livers, leading to increased expression of CDKN1A (p21WAF1/CIP1), which coincides with elevated expression and transcriptional activity of NRF2. Deleting Cdkn1a in SOCS1-deficient livers diminished NRF2 activation, oxidative stress and HCC progression. Elevated CDKN1A expression and enrichment of antioxidant response genes also characterized SOCS1-low/SOCS3-high HCC. SOCS1 expression in HCC cell lines reduced oxidative stress, p21 expression and NRF2 activation. Our findings demonstrate that SOCS1 controls the oncogenic potential of SOCS3-driven p53-p21-NRF2 axis and suggest that NRF2-mediated antioxidant response represents a drug target in SOCS1-deficient HCC.