Characterization of PHGDH expression in bladder cancer: potential targeting therapy with gemcitabine/cisplatin and the contribution of promoter DNA hypomethylation
Characterization of PHGDH expression in bladder cancer: potential targeting therapy with gemcitabine/cisplatin and the contribution of promoter DNA hypomethylation
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DOI：
10.1002/1878-0261.12697
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发表时间：
2020-05
影响因子：
6.6
通讯作者：
H. Yoshino;H. Enokida;Y. Osako;N. Nohata;Masaya Yonemori;S. Sugita;Kazuki Kuroshima;Masafumi Tsuruda;S. Tatarano;M. Nakagawa
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文献类型：
--
作者：
H. Yoshino;H. Enokida;Y. Osako;N. Nohata;Masaya Yonemori;S. Sugita;Kazuki Kuroshima;Masafumi Tsuruda;S. Tatarano;M. Nakagawa
d-3-磷酸甘油酸脱氢酶（PHGDH）在丝氨酸的合成中进行重要步骤。重要的是，PHGDH基因通常在某些癌症中扩增。我们以前的研究表明，PHGDH基因扩增与透明细胞肾细胞癌（ccRCC）的总体生存率低相关，并且通过PHGDH募集的丝氨酸合成的代谢重编程允许ccRCC细胞在不利的环境中生存。目前还没有研究PHGDH表达在膀胱癌（BC）中的作用。在这项调查中，我们研究了PHDGH在BC的临床意义。此外，我们询问PHGDH表达是否可以用于BC治疗。最后，我们研究了调节PHGDH表达的调控机制。使用来自癌症基因组图谱的数据，我们发现高级别BC患者的PHGDH表达水平显著高于低级别BC患者。此外，PHGDH高表达患者的生存期不如低表达患者长。在BC细胞系中通过si-RNA或抑制剂下调PHGDH显著抑制增殖能力并诱导凋亡。此外，使用PHGDH抑制剂和吉西他滨/顺铂的组合治疗与使用单一药剂相比在体外以及体内均实现协同肿瘤抑制。PHGDH调控机制分析表明，PHGDH的表达可能与DNA拷贝数和低甲基化在BC。这些发现表明，新的治疗策略可以用于BC。最后，我们的数据增强了我们对PHGDH在BC中的作用的理解。
d‐3‐Phosphoglycerate dehydrogenase (PHGDH) conducts an important step in the synthesis of serine. Importantly, the PHGDH gene is often amplified in certain cancers. Our previous studies revealed that PHGDH gene amplification was associated with poor overall survival in clear cell renal cell carcinoma (ccRCC) and that metabolic reprogramming of serine synthesis through PHGDH recruitment allowed ccRCC cells to survive in unfavorable environments. There have been no investigations of the role of PHGDH expression in bladder cancer (BC). In this investigation, we examined the clinical importance of PHDGH in BC. Furthermore, we asked whether PHGDH expression could be exploited for BC therapy. Finally, we investigated the regulatory mechanisms that modulated the expression of PHGDH. Using data from The Cancer Genome Atlas, we found that patients with high‐grade BC had significantly higher PHGDH expression levels than did those with low‐grade BC. In addition, patients with high PHGDH expression did not survive as long as those with low expression. PHGDH downregulation by si‐RNAs or an inhibitor in BC cell lines significantly inhibited proliferative ability and induced apoptosis. Furthermore, combined treatment using a PHGDH inhibitor and gemcitabine/cisplatin achieved synergistic tumor suppression compared to use of a single agent both in vitro as well as in vivo. Mechanistic analyses of PHGDH regulation showed that PHGDH expression might be associated with DNA copy number and hypomethylation in BC. These findings suggest novel therapeutic strategies could be used in BC. Finally, our data enhance our understanding of the role of PHGDH in BC.