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

Author:

Yu Zhenlong1ORCID,Peng Yulin1ORCID,Gao Jian23ORCID,Zhou Meirong1ORCID,Shi Lei1ORCID,Zhao Feng1ORCID,Wang Chao1ORCID,Tian Xiangge1ORCID,Feng Lei1ORCID,Huo Xiaokui1ORCID,Zhang Baojing1,Liu Min4,Fang Deyu5ORCID,Ma Xiaochi1ORCID

Affiliation:

1. College of Pharmacy, the Second Affiliated Hospital, Dalian Medical University, Dalian 116000, China.

2. Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou 221004, China.

3. School of Medicine, Anhui University of Science and Technology, Huainan 232001, China.

4. Neurology Department, Dalian University Affiliated Xinhua Hospital, Dalian 116021, China.

5. Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.

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.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

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