Chronic inflammation is associated with lung tumorigenesis, in which NF-κB-mediated epigenetic regulations play a critical role. Lung tumor suppressor 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 induces GPRC5A repression both in vitro and in vivo. Intriguingly, trans-activation of NF-κB downstream targets is not required, but the trans-activation domain of RelA/p65 was required for GPRC5A repression. NF-κB did not bind to any potential cis-element in GPRC5A promoter. Instead, p65 was complexed with RARα/β, and recruited to the RA-response element (RARE) site at the GPRC5A promoter, resulting in disrupted RNA polymerase II complex, and suppressed transcription. Noticeably, phosphorylation on Serine276 of p65 is required for interaction with RARα/β and repression of GPRC5A. Moreover, NF-κB-mediated epigenetic repression is through suppression of histone H3K9ac, but not DNA methylation of the CpG islands, at the GPRC5A promoter. Consistently, a HDAC inhibitor, but not DNA methylation inhibitor, restored GPRC5A expression in NSCLC cells. Thus, NF-κB induces transcriptional repression of GPRC5A via complex with RARα/β and mediates epigenetic repression via suppression of H3K9ac.
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, Yugene Chin, Qi Wang, Binhua P. Zhou, Jiong Deng