Downregulated METTL14 accumulates BPTF that reinforces super-enhancers and distal lung metastasis via glycolytic reprogramming in renal cell carcinoma.
Downregulated METTL14 accumulates BPTF that reinforces super-enhancers and distal lung metastasis via glycolytic reprogramming in renal cell carcinoma.
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作者：
Zhang C;Chen L;Liu Y;Huang J;Liu A;Xu Y;Shen Y;He H;Xu D
背景：甲基转移酶样14 （METTL14）参与多种恶性肿瘤的发生，但METTL14如何介导肾细胞癌（RCC）的转移尚未见报道。方法：采用Western blotting、实时荧光定量PCR、免疫组化检测相关基因mRNA及蛋白表达水平。利用甲基化RNA免疫沉淀测序和RNA测序技术筛选METTL14的潜在靶点。染色质免疫沉淀测序和转座酶可及的染色质测序测定用于研究表观遗传改变。在体外和体内通过细胞系、患者样本、异种移植模型和类器官证实了METTL14/BPTF促进肺转移的生物学作用和机制。结果：利用TCGA-KIRC和瑞金- rcc数据集，我们发现METTL14在mRCC样本中低表达，预示预后较差。METTL14缺乏促进了RCC的体内和体外转移。在机制上，mettl14介导的m6A修饰负调控溴域PHD指状转录因子（BPTF） mRNA的稳定性，并依赖BPTF驱动肺转移。mettl14缺陷细胞中积累的BPTF重塑了增强子景观，加强了几种致癌串扰。特别是，BPTF构成超增强子，激活下游靶标，如烯醇化酶2和SRC原癌基因非受体酪氨酸激酶，导致METTL14-/-细胞的糖酵解重编程。最后，我们确定了BPTF抑制剂AU1在抑制患者来源的细胞、mRCC来源的类器官（MDOs）和原位异种移植模型中的mRCC的功效。结论：我们的研究首次探讨了m6A修饰和METTL14/BPTF轴在mRCC的表观遗传和代谢重塑中的重要作用，强调了AU1是一个重要的治疗候选者。
Background: Methyltransferase-like 14 (METTL14) participates in tumorigenesis in several malignancies, but how METTL14 mediates the metastasis of renal cell carcinoma (RCC) has never been reported. Methods: Western blotting, quantitative real-time PCR, and immunohistochemistry were used to determine the mRNA and protein levels of relevant genes. Methylated RNA immunoprecipitation sequencing and RNA sequencing were utilized to screen potential targets of METTL14. Chromatin immunoprecipitation sequencing and assay for transposase-accessible chromatin sequencing were performed to investigate epigenetic alterations. The biological roles and mechanisms of METTL14/BPTF in promoting lung metastasis were confirmed in vitro and in vivo using cell lines, patient samples, xenograft models, and organoids. Results: Utilizing the TCGA-KIRC and Ruijin-RCC datasets, we found low expression of METTL14 in mRCC samples, which predicted poor prognosis. METTL14 deficiency promoted RCC metastasis in vitro and in vivo. Mechanistically, METTL14-mediated m6A modification negatively regulated the mRNA stability of bromodomain PHD finger transcription factor (BPTF) and depended on BPTF to drive lung metastasis. Accumulated BPTF in METTL14-deficient cells remodeled the enhancer landscape to reinforce several oncogenic crosstalk. Particularly, BPTF constituted super-enhancers that activate downstream targets like enolase 2 and SRC proto-oncogene nonreceptor tyrosine kinase, leading to glycolytic reprogramming of METTL14-/- cells. Finally, we determined the efficacy of the BPTF inhibitor AU1 in suppressing mRCC of patient-derived cells, mRCC-derived organoids (MDOs), and orthotopic xenograft models. Conclusions: Our study is the first to investigate the essential role of m6A modification and the METTL14/BPTF axis in the epigenetic and metabolic remodeling of mRCC, highlighting AU1 as a vital therapeutic candidate.
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影响因子：
29
作者：
Cascone T;McKenzie JA;Mbofung RM;Punt S;Wang Z;Xu C;Williams LJ;Wang Z;Bristow CA;Carugo A;Peoples MD;Li L;Karpinets T;Huang L;Malu S;Creasy C;Leahey SE;Chen J;Chen Y;Pelicano H;Bernatchez C;Gopal YNV;Heffernan TP;Hu J;Wang J;Amaria RN;Garraway LA;Huang P;Yang P;Wistuba II;Woodman SE;Roszik J;Davis RE;Davies MA;Heymach JV;Hwu P;Peng W
通讯作者：
Peng W
DOI：
10.1136/bmj.g4797
发表时间：
2014-11-10
期刊：
BMJ (Clinical research ed.)
影响因子：
--
作者：
Jonasch E;Gao J;Rathmell WK
通讯作者：
Rathmell WK
c-Src 通过激活 PFKFB3 促进肿瘤发生和肿瘤进展
影响因子：
8.8
作者：
Ma, Huanhuan;Zhang, Jia;Li, Qinxi
通讯作者：
Li, Qinxi
影响因子：
50.3
作者：
Andricovich J;Perkail S;Kai Y;Casasanta N;Peng W;Tzatsos A
通讯作者：
Tzatsos A
影响因子：
12.4
作者：
Laurette, Patrick;Coassolo, Sebastien;Davidson, Irwin
通讯作者：
Davidson, Irwin