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

Sci Adv. 2023 Jun 30;9(26):eade0387. doi: 10.1126/sciadv.ade0387. Epub 2023 Jun 30.

Abstract

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.

MeSH terms

  • Adenocarcinoma of Lung* / genetics
  • Carcinogenesis / genetics
  • Cell Transformation, Neoplastic
  • Cyclooxygenase 2 / genetics
  • HSP90 Heat-Shock Proteins / genetics
  • Humans
  • Lung Neoplasms* / genetics
  • Molecular Chaperones / genetics
  • Pyridinolcarbamate
  • Succinates
  • Succinic Acid
  • Transcription Factors / genetics

Substances

  • Succinic Acid
  • Transcription Factors
  • Cyclooxygenase 2
  • Pyridinolcarbamate
  • Succinates
  • Molecular Chaperones
  • HSP90 Heat-Shock Proteins