The p23 co-chaperone is a succinate-activated COX-2 transcription factor in lung adenocarcinoma tumorigenesis.
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| 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.
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| Authors | Zhenlong Yu, Yulin Peng, Jian Gao, Meirong Zhou, Lei Shi, Feng Zhao, Chao Wang, Xiangge Tian, Lei Feng, Xiaokui Huo, Baojing Zhang, Min Liu, Deyu Fang, Xiaochi Ma |
| Journal | Science advances (Sci Adv) Vol. 9 Issue 26 Pg. eade0387 (06 30 2023) ISSN: 2375-2548 [Electronic] United States |
| PMID | 37390202 (Publication Type: Journal Article) |
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