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Characterization of PHGDH expression in bladder cancer: potential targeting therapy with gemcitabine/cisplatin and the contribution of promoter DNA hypomethylation
- Source :
- Molecular Oncology, Molecular Oncology, Vol 14, Iss 9, Pp 2190-2202 (2020)
- Publication Year :
- 2020
- Publisher :
- John Wiley and Sons Inc., 2020.
-
Abstract
- 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.<br />This research investigated PHGDH, a key enzyme in the serine biosynthesis, in bladder cancer. PHGDH downregulation significantly inhibited cell proliferation, and the combined treatment between PHGDH inhibitor and gemcitabine/cisplatin achieved synergistic tumor suppressive effect compared to each single agent group both in vitro and in vivo. We also indicated that PHGDH was regulated by DNA copy number and hypomethylation.
- Subjects :
- 0301 basic medicine
Cancer Research
Deoxycytidine
0302 clinical medicine
PHGDH Gene
Phosphoglycerate dehydrogenase
Molecular Targeted Therapy
Promoter Regions, Genetic
PHGDH
Research Articles
Mice, Inbred BALB C
apoptosis
General Medicine
Methylation
lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Gene Expression Regulation, Neoplastic
Oncology
030220 oncology & carcinogenesis
Molecular Medicine
bladder cancer
Female
medicine.drug
Research Article
Down-Regulation
Mice, Nude
Antineoplastic Agents
Biology
lcsh:RC254-282
Gene Expression Regulation, Enzymologic
03 medical and health sciences
Downregulation and upregulation
Cell Line, Tumor
GC therapy
Genetics
medicine
Animals
Humans
RNA, Messenger
Phosphoglycerate Dehydrogenase
Cisplatin
DNA Methylation
medicine.disease
Gemcitabine
Clear cell renal cell carcinoma
030104 developmental biology
Urinary Bladder Neoplasms
Apoptosis
Cancer research
methylation
Subjects
Details
- Language :
- English
- ISSN :
- 18780261 and 15747891
- Volume :
- 14
- Issue :
- 9
- Database :
- OpenAIRE
- Journal :
- Molecular Oncology
- Accession number :
- edsair.doi.dedup.....e7835e3f6a353b1aefb0aaad110bd141