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The p23 co-chaperone is a succinate-activated COX-2 transcription factor in lung adenocarcinoma tumorigenesis.

Zhenlong YuYulin PengJian GaoMeirong ZhouLei ShiFeng ZhaoChao WangXiang-Ge TianLei FengXiao-Kui HuoBaojing ZhangMin LiuDeyu FangXiao-Chi Ma
Published in: Science advances (2023)
P23, historically known as a heat shock protein 90 (HSP90) co-chaperone, exerts some of its critical functions in an HSP90-independent manner, particularly when it translocates into the nucleus. The molecular nature underlying how this HSP90-independent p23 function is achieved remains as a biological mystery. Here, we found that p23 is a previously unidentified transcription factor of COX-2, and its nuclear localization predicts the poor clinical outcomes. Intratumor succinate promotes p23 succinylation at K7, K33, and K79, which drives its nuclear translocation for COX-2 transcription and consequently fascinates tumor growth. We then identified M16 as a potent p23 succinylation inhibitor from 1.6 million compounds through a combined virtual and biological screening. M16 inhibited p23 succinylation and nuclear translocation, attenuated COX-2 transcription in a p23-dependent manner, and markedly suppressed tumor growth. Therefore, our study defines p23 as a succinate-activated transcription factor in tumor progression and provides a rationale for inhibiting p23 succinylation as an anticancer chemotherapy.
Keyphrases
  • heat shock protein
  • transcription factor
  • heat shock
  • dna binding
  • genome wide identification
  • poor prognosis
  • clinical trial
  • locally advanced
  • squamous cell carcinoma
  • oxidative stress
  • anti inflammatory