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.

Document Type

Article

Publication Date

11-2022

Notes/Citation Information

© 2023, Song et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License

Digital Object Identifier (DOI)

https://doi.org/10.1172/jci.insight.153976

Funding Information

This work was supported by National Natural Science Foundation of China (81620108022, 91129303, 91729302, and 82172565 to J Deng; 91129733, 81502702 to QW; 81902313 to HS, 82002941 to BS, 31900441 to J Du, 82072570 to FY, and 82103571 to TW); by the Fundamental Research Funds for the Central Universities (to HS); and by the Youth Foundation of Shanghai Municipal Commission of Health and Family Planning (20164Y0261 to HS).

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