A p53/LINC00324 positive feedback loop suppresses tumor growth by counteracting SET-mediated transcriptional repression

Ling Zhang; Jun Zhang; Xiaofeng Xuan; Di Wu; Jianfeng Yu; Peizhen Wang; Xiaomei Yang; Jieru Zhang; Wenjuan Gan; Mengfan He; Xiao-Min Liu; Jun Zhou; Donglai Wang; Wei Gu; Dawei Li

doi:10.1016/j.celrep.2023.112833

A p53/LINC00324 positive feedback loop suppresses tumor growth by counteracting SET-mediated transcriptional repression

Cell Rep. 2023 Aug 29;42(8):112833. doi: 10.1016/j.celrep.2023.112833. Epub 2023 Jul 23.

Authors

Ling Zhang¹, Jun Zhang², Xiaofeng Xuan³, Di Wu¹, Jianfeng Yu⁴, Peizhen Wang¹, Xiaomei Yang⁵, Jieru Zhang³, Wenjuan Gan⁶, Mengfan He¹, Xiao-Min Liu², Jun Zhou², Donglai Wang⁷, Wei Gu⁸, Dawei Li⁹

Affiliations

¹ Center for Translational Medicine, The Affiliated Zhangjiagang Hospital of Soochow University, Suzhou Medical College of Soochow University, 68 Jiyang West Road, Suzhou 215600, China.
² School of Life Science and Technology, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, China.
³ Department of Respiratory & Critical Care Medicine, The Affiliated Zhangjiagang Hospital of Soochow University, Suzhou Medical College of Soochow University, 68 Jiyang West Road, Suzhou 215600, China.
⁴ Department of Life Science and Technology, Changshu Institute of Technology, 99 South Third Ring Road, Suzhou 215500, China.
⁵ Department of Emergency, The Affiliated Zhangjiagang Hospital of Soochow University, Suzhou Medical College of Soochow University, 68 Jiyang West Road, Suzhou 215600, China.
⁶ Department of Pathology, Dushu Lake Hospital Affiliated to Soochow University, 9 Chongwen Road, Suzhou 215300, China.
⁷ State Key Laboratory of Medical Molecular Biology and Department of Medical Genetics, Institute of Basic Medical Sciences and School of Basic Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China.
⁸ Institute for Cancer Genetics, and Department of Pathology and Cell Biology, and Herbert Irving Comprehensive Cancer Center, College of Physicians & Surgeons, Columbia University, 1130 St. Nicholas Avenue, New York, NY 10032, USA.
⁹ Center for Translational Medicine, The Affiliated Zhangjiagang Hospital of Soochow University, Suzhou Medical College of Soochow University, 68 Jiyang West Road, Suzhou 215600, China. Electronic address: daweili@suda.edu.cn.

PMID: 37480565
DOI: 10.1016/j.celrep.2023.112833

Abstract

The p53 tumor suppressor exerts antitumor functions through its ability to regulate the transcription of its downstream targets. Long noncoding RNAs (lncRNAs) act as oncogenes or tumor suppressors implicated in tumorigenesis and tumor progression. Here, we identify the lncRNA LINC00324 (long intergenic noncoding RNA 00324) as a direct p53 transcriptional target. Knockdown of LINC00324 expression promotes tumor growth by reducing p53 transcriptional activity, whereas ectopic LINC00324 expression demonstrates a reverse effect. Notably, LINC00324 is present in the endogenous p53 complex in tumor cells and directly binds to the C-terminal domain of p53 in vitro. Mechanistically, LINC00324 enables p53 transactivation by competitively disrupting the p53-SET interaction, resulting in an increase of p300/CBP-mediated H3K18 and H3K27 acetylation on the p53 target promoters. Lower LINC00324 expression is associated with more aggressive disease status and predicts worse overall survival of patients with cancer. Our study identifies a p53/LINC00324 positive feedback loop that suppresses tumor growth by counteracting SET-mediated transcriptional repression.

Keywords: CP: Cancer; LINC00324; SET; acetylation; lncRNAs; p300/CBP; p53; tumor suppression.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Feedback
Gene Expression
Humans
Neoplasms* / genetics
Oncogenes
RNA, Long Noncoding* / genetics
Tumor Suppressor Protein p53 / genetics

Substances

RNA, Long Noncoding
Tumor Suppressor Protein p53
TP53 protein, human