Inhibition of phosphoserine phosphatase enhances the anticancer efficacy of 5-fluorouracil in colorectal cancer

Li, Xin; Xun, Zhe; Yang, Yong

doi:10.1016/j.bbrc.2016.06.112

Cited by 15 publications

(13 citation statements)

References 20 publications

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“…From a total of 426 genes located on chromosome 7p, we extracted 20 candidate genes that satisfied the two criteria: 1) overexpression in tumor tissues compared to non-neoplastic tissues (NNT) of colorectal mucosa (> 1.5-fold change, Mann-Whitney U test p < 0.01) and 2) positive correlation between DNA copy number and mRNA expression levels (Pearson correlation >0.4, p < 0.01). These candidates included several genes that had been reported as oncogenes in CRC (i.e., NFE2L3 , MACC1 , and PSPH ) [[45], [46], [47]]. Among these 20 genes, eIF5-mimic protein 1 ( 5MP1 ), also known as basic leucine zipper and W2 domains 2 ( BZW2 ), was located on the residue 7p21.1.…”

Section: Resultsmentioning

confidence: 99%

Novel oncogene 5MP1 reprograms c-Myc translation initiation to drive malignant phenotypes in colorectal cancer

Sato

Masuda

et al. 2019

eBioMedicine

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Background Translational reprogramming through controlled initiation from non-AUG start codons is considered a crucial driving force in tumorigenesis and tumor progression. However, its clinical impact and underlying mechanism are not fully understood. Methods Using a bioinformatics approach, we identified translation initiation regulator 5MP1/BZW2 on chromosome 7p as a potential oncogenic driver gene in colorectal cancer (CRC), and explored the biological effect of 5MP1 in CRC in vitro or in vivo. Pathway analysis was performed to identify the downstream target of 5MP1, which was verified with transcriptomic and biochemical analyses. Finally, we assessed the clinical significance of 5MP1 expression in CRC patients. Findings 5MP1 was ubiquitously amplified and overexpressed in CRC. 5MP1 promoted tumor growth and induced cell cycle progression of CRC. c-Myc was identified as its potential downstream effector. c-Myc has two in-frame start codons, AUG and CUG (non-AUG) located upstream of the AUG. 5MP1 expression increased the AUG-initiated c-Myc isoform relative to the CUG-initiated isoform. The AUG-initiated c-Myc isoform displayed higher protein stability and a stronger transactivation activity for oncogenic pathways than the CUG-initiated isoform, accounting for 5MP1 -driven cell cycle progression and tumor growth. Clinically, high 5MP1 expression predicts poor survival of CRC patients. Interpretation 5MP1 is a novel oncogene that reprograms c-Myc translation in CRC. 5MP1 could be a potential therapeutic target to overcome therapeutic resistance conferred by tumor heterogeneity of CRC. Fund Japan Society for the Promotion of Science; Priority Issue on Post-K computer; National Institutes of Health; National Science Foundation; KSU Johnson Cancer Center.

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Section: Resultsmentioning

confidence: 99%

Novel oncogene 5MP1 reprograms c-Myc translation initiation to drive malignant phenotypes in colorectal cancer

Sato

Masuda

et al. 2019

eBioMedicine

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“…Clinical studies have shown that PSPH overexpression is a promising prognostic and predictive biomarker for advanced colorectal cancer, hepatocellular carcinoma, breast cancer, endometrial cancer and thyroid cancer patients 11, 17-20. Another report demonstrated that suppression of PSPH could increase the sensitivity to 5-fluorouracil in colorectal cancer 21. The proposed mechanism for improved colorectal cancer efficacy involves the depletion of PSPH-mediated serine synthesis and glutathione reservoirs, resulting in the increased accumulation of 5-fluorouracil induced reactive oxygen species.…”

Section: Discussionmentioning

confidence: 99%

PSPH Mediates the Metastasis and Proliferation of Non-small Cell Lung Cancer through MAPK Signaling Pathways

Liao¹,

Ge²,

Zhan³

et al. 2019

Int. J. Biol. Sci.

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Growing evidence indicates that phosphoserine phosphatase (PSPH) is up-regulated and correlates with prognosis in multiple types of cancer. However, little is known about the roles of PSPH in NSCLC. Thus, the aim of the present study was to demonstrate the expression of PSPH in human NSCLC and reveal its biological functions and the underlying mechanisms. qRT-PCR, western blot and immunohistochemistry were used to assess the expression of NSCLC patient specimens and NSCLC cell lines. The functions of PSPH in migration and invasion were determined using trans-well and wound-healing assays. Cell proliferation capacity was performed by cell counting kit-8 (CCK-8), colony formation assays and cell cycle analysis. We demonstrated that PSPH was overexpressed in NSCLC specimens compared with the adjacent non-tumorous specimens, and high expression of PSPH was associated with clinical stage, metastasis and gender in NSCLC. Decreased expression of PSPH inhibited NSCLC cells migration, invasion and proliferation. Most importantly, further experiments demonstrated that PSPH might regulate NSCLC progress through MAPK signaling pathways. Lastly, immunohistochemistry (IHC) revealed that the PSPH expression level was positively correlated with the clinical stage in NSCLC patients. These results suggest that PSPH may act as a putative oncogene and a potential therapeutic target in NSCLC.

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“…The first serine-synthetic enzyme PHGDH was reported to promote pancreatic [10] and breast cancer [11]. Overexpression of PSPH was found in hepatocellular cancer [12] and colorectal cancer [13]. PSAT1 mediates carbon metabolism and the TCA cycle, which provides energy and increases biomass in non-small cell lung cancer (NSCLC) [14], breast cancer [16] and colorectal cancer [17].…”

Section: Phgdh Psph and Psat1 Are Important Regulators Of The Ssp Amentioning

confidence: 99%

“…PSPH is a c-Myc-mediated enzyme and increases as hepatocellular carcinoma progression to a malignant clinical stage [12]. Moreover, overexpression of PSPH is also a poor prognostic marker in colorectal cancer [13].…”

Section: Introductionmentioning

confidence: 99%

Overexpression of PSAT1 Gene is a Favorable Prognostic Marker in Lower-Grade Gliomas and Predicts a Favorable Outcome in Patients with IDH1 Mutations and Chromosome 1p19q Codeletion

Huang

Chan

Lin

2019

Cancers

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Patients with lower-grade gliomas (LGGs) have highly diverse clinical outcomes. Although histological features and molecular markers have been used to predict prognosis, the identification of new biomarkers for the accurate prediction of patient outcomes is still needed. The serine synthesis pathway (SSP) is important in cancer metabolism. There are three key regulators, including phosphoglycerate dehydrogenase (PHGDH), phosphoserine phosphatase (PSPH), and phosphoserine aminotransferase 1 (PSAT1), in SSP. However, their clinical importance in LGGs is still unknown. In this study, we used the bioinformatics tool in the Gene Expression Profiling Interactive Analysis (GEPIA) website to examine the prognostic significance of PHGDH, PSPH, and PSAT1 genes in LGGs. PSAT1 gene expression was then identified as a potential biomarker candidate for LGGs. Datasets from The Cancer Genome Atlas (TCGA) and the Chinese Glioma Genome Atlas (CGGA) were further used to explore the prognostic role of PSAT1 gene. Our results demonstrated that PSAT1 overexpression is a favorable prognostic marker of LGGs and significantly correlated with patient age ≤40, and a lower WHO histological grade, as well as mutations in IDH1, TP53 and ATRX, but not with chromosome 1p19q codeletions. More importantly, LGG patients with isocitrate dehydrogenase 1 (IDH1) mutations, chromosome 1p19q codeletions, and PSAT1 overexpression may have the best overall survival (five-year survival rate: 100%). Finally, we observed a coordinated biological reaction between IDH1 mutations and PSAT1 overexpression, and suggested overexpression of PSAT1 might enhance the function of mutant IDH1 to promote a favorable outcome in LGG patients. In conclusion, our study confirmed the importance of identifying the overexpression of PSAT1 as a favorable prognostic marker of LGGs, which may compensate for the limitation of IDH1 mutations and chromosome 1p19q codeletion in the prognostication of LGGs.

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Inhibition of phosphoserine phosphatase enhances the anticancer efficacy of 5-fluorouracil in colorectal cancer

Cited by 15 publications

References 20 publications

Novel oncogene 5MP1 reprograms c-Myc translation initiation to drive malignant phenotypes in colorectal cancer

Novel oncogene 5MP1 reprograms c-Myc translation initiation to drive malignant phenotypes in colorectal cancer

PSPH Mediates the Metastasis and Proliferation of Non-small Cell Lung Cancer through MAPK Signaling Pathways

Overexpression of PSAT1 Gene is a Favorable Prognostic Marker in Lower-Grade Gliomas and Predicts a Favorable Outcome in Patients with IDH1 Mutations and Chromosome 1p19q Codeletion

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