Nuclear PKM2 promotes the progression of oral squamous cell carcinoma by inducing EMT and post-translationally repressing TGIF2.
Nuclear PKM2 promotes the progression of oral squamous cell carcinoma by inducing EMT and post-translationally repressing TGIF2.
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DOI：
10.18632/oncotarget.25850
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发表时间：
2018-09-18
期刊：
影响因子：
--
通讯作者：
Hashimoto S
中科院分区：
文献类型：
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作者：
Tanaka F;Yoshimoto S;Okamura K;Ikebe T;Hashimoto S
丙酮酸激酶M2（PKM 2）是一种糖酵解酶，其作为导致能量产生的代谢功能对癌症进展至关重要，称为瓦尔堡效应。在这项研究中，我们发现PKM 2作为一种非代谢功能，通过诱导上皮-间质转化（EMT）和翻译后TGF-2降解来促进人类口腔鳞状细胞癌（OSCC）中癌细胞的进展，这对癌细胞侵袭的潜力至关重要。PKM 2免疫反应在浸润性癌细胞胞浆中较强，在具有EMT特征的梭形癌细胞胞核中较强。TGF-2核免疫反应在发育不良的上皮细胞中被观察到，但在癌细胞中被抑制。在体外分析中，PKM 2的胞质表达易位到细胞核中的人OSCC衍生的HSC-4和SAS细胞当EMT刺激。此外，TGIF 2的核表达在EMT诱导的HSC-4和SAS细胞中被明显抑制。我们认识到在EMT诱导的HSC-4和SAS细胞中TGIF 2蛋白和mRNA表达的不匹配，并且通过MG 132蛋白酶体抑制测定发现TGIF 2蛋白通过泛素蛋白酶体系统被后降解。最后，在PKM 2敲低测定中确认PKM 2促进HSC-4和SAS细胞进展。因此，我们阐明了PKM 2的非代谢功能的新机制，以促进OSCC的进展，通过PKM 2核转位，随后诱导EMT，并通过泛素蛋白酶体系统抑制TGF-2的表达。
Pyruvate kinase M2 (PKM2), a glycolytic enzyme, acts as a metabolic function leading to an energy production critical for cancer progression, known as Warburg effect. In this study we showed a pivotal role of PKM2 acting as a non-metabolic function to promote cancer cell progression in human oral squamous cell carcinoma (OSCC) through the induction of epithelial-mesenchymal transition (EMT), which is crucial for the potential in cancer cell invasion, and post-translational TGIF2 degradation. PKM2 immunoreaction was strong in the cytoplasm of invasive cancer cells, and distinct in the nucleus of spindle-shaped cancer cells with EMT characteristics. TGIF2 nuclear immunoreaction was seen in dysplastic epithelial cells but was repressed in cancer cells. In vitro analyses, cytoplasmic expression of PKM2 was translocated into the nucleus in human OSCC derived HSC-4 and SAS cells when EMT was stimulated. In addition, nuclear expression of TGIF2 was distinctively repressed in EMT induced HSC-4 and SAS cells. We recognized a mismatch in TGIF2 protein and mRNA expression in EMT induced HSC-4 and SAS cells and found that TGIF2 protein was post-translationally degraded through a ubiquitin proteasome system by an MG132 proteasome inhibition assay. Finally, promotion of HSC-4 and SAS cell progression by PKM2 was recognized in PKM2 knockdown assays. Thus, we clarified a new mechanism of non-metabolic function of PKM2 to promote the progression of OSCC through PKM2 nuclear translocation, subsequently induced EMT, and post-translationally repressed TGIF2 expression by a ubiquitin proteasome system.