NF-κB represses retinoic acid receptor-mediated GPRC5A transactivation in lung epithelial cells to promote neoplasia.
NF-κB represses retinoic acid receptor-mediated GPRC5A transactivation in lung epithelial cells to promote neoplasia.
复制标题
NFκB 诱导肺上皮细胞中 GPRC5A 的表观遗传抑制，促进肿瘤形成
DOI：
10.1172/jci.insight.153976
复制
发表时间：
2023-01-10
期刊：
影响因子：
8
通讯作者：
Deng, Jiong
中科院分区：
文献类型：
--
作者：
Song, Hongyong;Ye, Xiaofeng;Liao, Yueling;Zhang, Siwei;Xu, Dongliang;Zhong, Shuangshuang;Jing, Bo;Wang, Tong;Sun, Beibei;Xu, Jianhua;Guo, Wenzheng;Li, Kaimi;Hu, Min;Kuang, Yanbin;Ling, Jing;Zhang, Tuo;Wu, Yadi;Du, Jing;Yao, Feng;Chin, Y. Eugene;Wang, Qi;Zhou, Binhua P.;Deng, Jiong
慢性炎症与肺肿瘤的发生有关，其中NF-κ B介导的表观遗传调控起着关键作用。肺肿瘤抑制因子G蛋白偶联受体，C家族，成员5A（GPRC5A），在大多数非小细胞肺癌（NSCLC）中受到抑制;然而，其机制仍不清楚。在此，我们发现NF-κ B在抑制GPRC 5A中起着转录抑制因子的作用。NF-κ B在体外和体内均可诱导GPRC 5A的抑制。有趣的是，NF-κ B下游靶点的反式激活不是必需的，但是RelA/p65的反式激活结构域是GPRC 5A抑制所必需的。NF-κ B不与GPRC 5A启动子中的任何潜在顺式元件结合。相反，p65与视黄酸受体α/β（RAR α/β）复合，并被募集到GPRC5A启动子的RA反应元件位点，导致RNA聚合酶II复合被破坏并抑制转录。值得注意的是，p65的丝氨酸276上的磷酸化是与RAR α/β相互作用和GPRC5A抑制所必需的。此外，NF-κ B介导的表观遗传抑制是通过抑制GPRC5A启动子处的乙酰化组蛋白H3K9（H3K9ac），而不是CpG岛的DNA甲基化。Consistent是一种组蛋白去乙酰化酶抑制剂，但不是DNA甲基化抑制剂，可恢复NSCLC细胞中GPRC5A的表达。因此，NF-κ B通过与RAR α/β的复合物诱导GPRC 5A的转录抑制，并通过抑制H3 K9ac介导表观遗传抑制。
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.
登录
查看更多内容
影响因子：
4.8
作者：
Austenaa, LMI;Carlsen, H;Blomhoff, R
通讯作者：
Blomhoff, R
影响因子：
4.8
作者：
Cheng, YJ;Lotan, R
通讯作者：
Lotan, R
影响因子：
4
作者：
Goyal, Umesh;Ta, Malancha
通讯作者：
Ta, Malancha
影响因子：
11.2
作者：
Chen Y;Deng J;Fujimoto J;Kadara H;Men T;Lotan D;Lotan R
通讯作者：
Lotan R
影响因子：
7.5
作者：
Qiu, Shujuan;Chen, Xuexun;Zhang, Zhaoguang
通讯作者：
Zhang, Zhaoguang