NF-<bold>κ</bold>B represses retinoic acid receptor–mediated GPRC5A transactivation in lung epithelial cells to promote neoplasia

Hongyong Song, Xiaofeng Ye, Yueling Liao, Siwei Zhang, Dongliang Xu, Shuangshuang Zhong, Bo Jing, Tong Wang, Beibei Sun, Jianhua Xu, Wenzheng Guo, Kaimi Li, Min Hu, Yanbin Kuang, Jing Ling, Tuo Zhang, Yadi Wu, Jing Du, Feng Yao, Y. Eugene ChinQi Wang, Binhua P. Zhou, Jiong Deng

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

Chronic inflammation is associated with lung tumorigenesis, in which NF-κB–mediated epigenetic regulation plays a critical role. Lung tumor suppressor G protein–coupled receptor, family C, member 5A (GPRC5A), is repressed in most non–small cell lung cancer (NSCLC); however, the mechanisms remain unclear. Here, we show that NF-κB acts as a transcriptional repressor in suppression of GPRC5A. NF-κB induced GPRC5A repression both in vitro and in vivo. Intriguingly, transactivation of NF-κB downstream targets was not required, but the transactivation domain of RelA/p65 was required for GPRC5A repression. NF-κB did not bind to any potential cis-element in the GPRC5A promoter. Instead, p65 was complexed with retinoic acid receptor α/β (RARα/β) and recruited to the RA response element site at the GPRC5A promoter, resulting in disrupted RNA polymerase II complexing and suppressed transcription. Notably, phosphorylation on serine 276 of p65 was required for interaction with RARα/β and repression of GPRC5A. Moreover, NF-κB–mediated epigenetic repression was through suppression of acetylated histone H3K9 (H3K9ac), but not DNA methylation of the CpG islands, at the GPRC5A promoter. Consistently, a histone deacetylase inhibitor, but not DNA methylation inhibitor, restored GPRC5A expression in NSCLC cells. Thus, NF-κB induces transcriptional repression of GPRC5A via a complex with RARα/β and mediates epigenetic repression via suppression of H3K9ac.

Original languageEnglish
Article numbere153976
JournalJCI insight
Volume8
Issue number1
DOIs
StatePublished - Jan 10 2023

Bibliographical note

Publisher Copyright:
© 2023, Song et al.

ASJC Scopus subject areas

  • General Medicine

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