TY - JOUR
T1 - NF-κB represses retinoic acid receptor–mediated GPRC5A transactivation in lung epithelial cells to promote neoplasia
AU - Song, Hongyong
AU - Ye, Xiaofeng
AU - Liao, Yueling
AU - Zhang, Siwei
AU - Xu, Dongliang
AU - Zhong, Shuangshuang
AU - Jing, Bo
AU - Wang, Tong
AU - Sun, Beibei
AU - Xu, Jianhua
AU - Guo, Wenzheng
AU - Li, Kaimi
AU - Hu, Min
AU - Kuang, Yanbin
AU - Ling, Jing
AU - Zhang, Tuo
AU - Wu, Yadi
AU - Du, Jing
AU - Yao, Feng
AU - Chin, Y. Eugene
AU - Wang, Qi
AU - Zhou, Binhua P.
AU - Deng, Jiong
N1 - Publisher Copyright:
© 2023, Song et al.
PY - 2023/1/10
Y1 - 2023/1/10
N2 - 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.
AB - 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.
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U2 - 10.1172/jci.insight.153976
DO - 10.1172/jci.insight.153976
M3 - Article
C2 - 36413416
AN - SCOPUS:85145971099
VL - 8
JO - JCI insight
JF - JCI insight
IS - 1
M1 - e153976
ER -