Citrullination modulation maintains HIF-1A stabilization to drive tumor progression

HIF-1 (Hypoxia-inducible factor 1) is the master regulator responding to hypoxic conditions. Here, we found that HIF-1A is citrullinated by peptidyl arginine deiminase 4 (PADI4) at arginine 698, promoting HIF-1A stabilization and thus HIF-1-driven tumor growth. The knockdown of PADI4 could dramatically decrease HIF-1 protein expression without affecting the mRNA level, and this could be rescued by the proteasome inhibitor MG132 treatment under hypoxia. And PADI4-HIF-1A interaction is critical for HIF-1A stability and tumor progression, depending on the enzymatic activity of PADI4 and the pocket structure of PADI4. DHE, an FDA-approved agent for the treatment of migraine, was found serve as a potential antitumor agent throgh disrupting PADI4-HIF-1A interaction and suppressing HIF-1A stability. Taken together, we found the anti-tumor effect of DHE due to its effect on blocking PADI4-HIF-1A interaction and downregulating HIF-1A pathway in cancer cells. To figure out the influence of DHE on liver cancer cell under hypoxia, we treated Hep3B cell lines with two does DHE in 6 hours under Hypoxia and extracted mRNA for furthur RNA seq.