The RNA methyltransferase METTL16 enhances cholangiocarcinoma growth through PRDM15-mediated FGFR4 expression.
The RNA methyltransferase METTL16 enhances cholangiocarcinoma growth through PRDM15-mediated FGFR4 expression.
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DOI：
10.1186/s13046-023-02844-5
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发表时间：
2023-10-11
影响因子：
11.3
通讯作者：
Wu, Tong
中科院分区：
文献类型：
--
作者：
Liu, Nianli;Zhang, Jinqiang;Chen, Weina;Ma, Wenbo;Wu, Tong
RNA N6-甲基腺苷（m6 A）修饰与包括胆管癌（CCA）在内的人类癌症的进展有关。最近，BELL 16被鉴定为一种负责m6 A修饰的新RNA甲基转移酶，尽管BELL 16在CCA中的作用尚未得到研究。本研究旨在探讨RNA甲基转移酶胃L16在CCA中的作用及其机制。通过分析公开可用的数据集或通过对肿瘤样品进行IHC染色来检查CCA中的胃L16的表达。在体外和体内进行siRNA或CRISPR/Cas9介导的功能丧失研究，以研究CCA中胃L16的致癌作用。进行MeRIP-Seq以鉴定胃L16的下游靶标。采用ChIP-qPCR、免疫共沉淀和免疫印迹等方法研究胃窦L16在CCA中的表达调控机制。我们观察到，在人CCA组织中，胃L16的表达显著增加。胃L16的耗尽显著抑制CCA细胞增殖并降低肿瘤进展。PRDM 15被鉴定为CCA细胞中胃L16的关键靶标。从机制上讲，我们的数据表明，胃L16通过YTHDF 1依赖性翻译调节PRDM 15蛋白表达。因此，我们观察到PRDM 15表达的恢复可以挽救由胃L16消耗诱导的CCA细胞增殖/集落形成的缺陷。我们随后的分析表明，胃L16-PRDM 15信号调节CCA细胞中FGFR 4的表达。具体而言，我们观察到PRDM 15蛋白与FGFR 4启动子相关以调节其表达。此外，我们发现组蛋白乙酰转移酶p300与转录因子YY 1协同作用，通过组蛋白H3赖氨酸27（H3 K27）乙酰化来调节CCA细胞中胃L16基因的表达。这项研究描述了一种新的胃L16-PRDM 15-FGFR 4信号传导轴，它对CCA生长至关重要，可能具有重要的治疗意义。我们发现，耗尽的胃L16显着抑制CCA细胞增殖和减少肿瘤进展。在线版本包含补充材料，可通过10.1186/s13046-023-02844-5获得。
RNA N6-Methyladenosine (m6A) modification is implicated in the progression of human cancers including cholangiocarcinoma (CCA). METTL16 is recently identified as a new RNA methyltransferase responsible for m6A modification, although the role of METTL16 in CCA has not yet been examined. The current study aims to investigate the effect and mechanism of the RNA methyltransferase METTL16 in CCA. The expression of METTL16 in CCA was examined by analyzing publicly available datasets or by IHC staining on tumor samples. siRNA or CRISPR/Cas9-mediated loss of function studies were performed in vitro and in vivo to investigate the oncogenic role of METTL16 in CCA. MeRIP-Seq was carried out to identify the downstream target of METTL16. ChIP-qPCR, immunoprecipitation, and immunoblots were used to explore the regulation mechanisms for METTL16 expression in CCA. We observed that the expression of METTL16 was noticeably increased in human CCA tissues. Depletion of METTL16 significantly inhibited CCA cell proliferation and decreased tumor progression. PRDM15 was identified as a key target of METTL16 in CCA cells. Mechanistically, our data showed that METTL16 regulated PRDM15 protein expression via YTHDF1-dependent translation. Accordingly, we observed that restoration of PRDM15 expression could rescue the deficiency of CCA cell proliferation/colony formation induced by METTL16 depletion. Our subsequent analyses revealed that METTL16-PRDM15 signaling regulated the expression of FGFR4 in CCA cells. Specifically, we observed that PRDM15 protein was associated with the FGFR4 promoter to regulate its expression. Furthermore, we showed that the histone acetyltransferase p300 cooperated with the transcription factor YY1 to regulate METTL16 gene expression via histone H3 lysine 27 (H3K27) acetylation in CCA cells. This study describes a novel METTL16-PRDM15-FGFR4 signaling axis which is crucial for CCA growth and may have important therapeutic implications. We showed that depletion of METTL16 significantly inhibited CCA cell proliferation and decreased tumor progression. The online version contains supplementary material available at 10.1186/s13046-023-02844-5.
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DOI：
10.1038/s41572-021-00300-2
发表时间：
2021-09-09
期刊：
Nature reviews. Disease primers
影响因子：
--
作者：
通讯作者：
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DOI：
10.1073/pnas.2002672117
发表时间：
2020-07-14
影响因子：
11.1
作者：
Manieri, Elisa;Folgueira, Cintia;Sabio, Guadalupe
通讯作者：
Sabio, Guadalupe
影响因子：
13.5
作者：
Ma, Wenbo;Han, Chang;Wu, Tong
通讯作者：
Wu, Tong
DOI：
10.1002/hep.31410
发表时间：
2021-01
期刊：
Hepatology (Baltimore, Md.)
影响因子：
--
作者：
Fabris L;Sato K;Alpini G;Strazzabosco M
通讯作者：
Strazzabosco M
影响因子：
4
作者：
Phillips AJ;Lobl MB;Hafeji YA;Safranek HR;Mohr AM;Mott JL
通讯作者：
Mott JL