Nur77-activated lncRNA WFDC21P attenuates hepatocarcinogenesis via modulating glycolysis
Nur77-activated lncRNA WFDC21P attenuates hepatocarcinogenesis via modulating glycolysis
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Nur77 激活的 lncRNA WFDC21P 通过调节糖酵解来减弱肝癌的发生。
DOI：
10.1038/s41388-020-1158-y
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发表时间：
2020-01-20
期刊：
影响因子：
8
通讯作者：
Chen, Hang-zi
中科院分区：
文献类型：
--
作者：
Guan, Yun-feng;Huang, Qiao-ling;Chen, Hang-zi
肝细胞癌（HCC）是全球癌症相关死亡的主要原因之一。孤儿核受体Nur77在HCC中低表达，可作为肿瘤抑制因子抑制HCC。然而，其具体机制仍不清楚。在这里，我们证明Nur77可以通过转录激活lncRNA WAP四二硫核结构域21假基因（WFDC21P）来抑制HCC的发展。Nur77与其应答元件结合在WFDC21P启动子上，直接诱导WFDC21P转录，在体外和体内均可抑制HCC细胞增殖、肿瘤生长和肿瘤转移。在临床HCC样本中，WFDC21P的表达与Nur77呈正相关，WFDC21P的缺失与较差的预后相关。机制上，WFDC21P可以通过与糖酵解的两个关键酶PFKP和PKM2同时相互作用来抑制糖酵解。这些相互作用不仅破坏PFKP的四聚体形成，阻碍其催化活性，而且阻止PKM2的核易位，抑制其作为转录辅激活因子的功能。细胞孢素- b （Cytosporone-B, Csn-B）是Nur77的激动剂，可以刺激WFDC21P的表达，并以WFDC21P依赖的方式抑制HCC。因此，我们的研究揭示了一种新的HCC抑制因子，并将HCC的糖酵解重构与Nur77-WFDC21P-PFKP/PKM2轴联系起来。
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality worldwide. Orphan nuclear receptor Nur77, which is low expressed in HCC, functions as a tumor suppressor to suppress HCC. However, the detailed mechanism is still not well understood. Here, we demonstrate that Nur77 could inhibit HCC development via transcriptional activation of the lncRNA WAP four-disulfide core domain 21 pseudogene (WFDC21P). Nur77 binds to its response elements on the WFDC21P promoter to directly induce WFDC21P transcription, which inhibits HCC cell proliferation, tumor growth, and tumor metastasis both in vitro and in vivo. In clinical HCC samples, WFDC21P expression positively correlated with that of Nur77, and the loss of WFDC21P is associated with worse prognosis. Mechanistically, WFDC21P could inhibit glycolysis by simultaneously interacting with PFKP and PKM2, two key enzymes in glycolysis. These interactions not only abrogate the tetramer formation of PFKP to impede its catalytic activity but also prevent the nuclear translocation of PKM2 to suppress its function as a transcriptional coactivator. Cytosporone-B (Csn-B), an agonist for Nur77, could stimulate WFDC21P expression and suppress HCC in a WFDC21P-dependent manner. Therefore, our study reveals a new HCC suppressor and connects the glycolytic remodeling of HCC with the Nur77-WFDC21P-PFKP/PKM2 axis.