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 re-programming of serine synthesis through PHGDH recruitment allowed ccRCC cells to survive in unfavourable 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 hypo-methylation 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.
Molecular oncology. 2020 May 09 [Epub ahead of print]
Hirofumi Yoshino, Hideki Enokida, Yoichi Osako, Nijiro Nohata, Masaya Yonemori, Satoshi Sugita, Kazuki Kuroshima, Masafumi Tsuruda, Shuichi Tatarano, Masayuki Nakagawa
Department of Urology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan., MSD K.K, Tokyo, Japan.