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

Khan, M. M.; Boufaied, N.; Yeganeh, M.; Ghosh, A.; Kandhi, R.; Bagheri, R.; Petkiewicz, S.; Sharma, A.; Yoshimura, A.; Ferbeyre, G.; Labbe, D. P.; Ramanathan, S.; Ilangumaran, S.

doi:10.1101/2021.10.21.465149

bioRxiv · 10.1101/2021.10.21.465149

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

Khan, M. M.·Boufaied, N.·Yeganeh, M.·Ghosh, A.·Kandhi, R.·Bagheri, R.·Petkiewicz, S.·Sharma, A.·Yoshimura, A.·Ferbeyre, G.·Labbe, D. P.·Ramanathan, S.·Ilangumaran, S.

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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.

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Khan, M. M., Boufaied, N., Yeganeh, M., Ghosh, A., Kandhi, R., Bagheri, R., Petkiewicz, S., Sharma, A., Yoshimura, A., Ferbeyre, G., Labbe, D. P., Ramanathan, S., Ilangumaran, S.. 2021-10-21. SOCS3-mediated activation of p53-p21-NRF2 axis and cellular adaptation to oxidative stress in SOCS1-deficient hepatocellular carcinoma. https://doi.org/10.1101/2021.10.21.465149

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