p53 Protein-mediated Regulation of Phosphoglycerate Dehydrogenase (PHGDH) Is Crucial for the Apoptotic Response upon Serine Starvation

Ou, Yvonne; Wang, Shang–Jui; Jiang, Lei; Zheng, Bin; Gu, Wei

doi:10.1074/jbc.m114.616359

Cited by 110 publications

(98 citation statements)

References 37 publications

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“…To identify metabolic targets of p53, the melanoma cell line A375 expressing wild-type p53 was either untreated or treated with Nutlin, and total RNA derived from these cells was subjected to RNA sequencing. In our previous study, we identified PHGDH from the RNA-sequencing result as a metabolic target of p53 that is critical for inducing the apoptotic response upon serine starvation (15). In addition, we also found that mRNA levels of SAT1 are significantly up-regulated upon p53 activation (Fig.…”

Section: Sat1mentioning

confidence: 67%

“…ChIP assays were performed as previously described in H1299 cells transfected with empty vector or pCIN4-p53 (15). Primers used for ChIP qPCR were SAT RE1 forward 5′-CAGTAGGGTTTCCGCCAAG-3′, SAT1 RE1 reverse 5′-AACCCGGAGGACAAAAGTG-3′; SAT RE2 forward 5′-TCCTGA-GTTTGCTTCCCACT-3′, SAT1 RE2 reverse 5′-GGTGTGTCCCCCAGTAACAT-3′; SAT RE3 forward 5′-CACTGATTCTCAACTGCCAAA-3′, SAT1 RE3 reverse 5′-CAGAAGCAGAGGAGGAAAAGG-3′; SAT RE4 forward 5′-CAAAAG-ACCACCCCTCACAT-3′, SAT1 RE4 reverse 5′-CCTAGGGCAGGAAGGGTAAC-3′;…”

Section: Methodsmentioning

confidence: 99%

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Activation of SAT1 engages polyamine metabolism with p53-mediated ferroptotic responses

Wang

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Although p53-mediated cell-cycle arrest, senescence, and apoptosis remain critical barriers to cancer development, the emerging role of p53 in cell metabolism, oxidative responses, and ferroptotic cell death has been a topic of great interest. Nevertheless, it is unclear how p53 orchestrates its activities in multiple metabolic pathways into tumor suppressive effects. Here, we identified the SAT1 (spermidine/spermine N 1 -acetyltransferase 1) gene as a transcription target of p53. SAT1 is a rate-limiting enzyme in polyamine catabolism critically involved in the conversion of spermidine and spermine back to putrescine. Surprisingly, we found that activation of SAT1 expression induces lipid peroxidation and sensitizes cells to undergo ferroptosis upon reactive oxygen species (ROS)-induced stress, which also leads to suppression of tumor growth in xenograft tumor models. Notably, SAT1 expression is down-regulated in human tumors, and CRISPRcas9-mediated knockout of SAT1 expression partially abrogates p53-mediated ferroptosis. Moreover, SAT1 induction is correlated with the expression levels of arachidonate 15-lipoxygenase (ALOX15), and SAT1-induced ferroptosis is significantly abrogated in the presence of PD146176, a specific inhibitor of ALOX15. Thus, our findings uncover a metabolic target of p53 involved in ferroptotic cell death and provide insight into the regulation of polyamine metabolism and ferroptosis-mediated tumor suppression.SAT1 | p53 | polyamine metabolism | ferroptosis | tumor suppression

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Section: Sat1mentioning

confidence: 67%

Section: Methodsmentioning

confidence: 99%

Activation of SAT1 engages polyamine metabolism with p53-mediated ferroptotic responses

Wang

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

550

442

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“…In addition, TP53 promotes metabolic remodeling under serine starvation for cell proliferation (18,19). MDM2 also regulates serine metabolism during oxidative stress independent of p53 (20).…”

Section: Introductionmentioning

confidence: 99%

SHMT2 Desuccinylation by SIRT5 Drives Cancer Cell Proliferation

et al. 2018

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The mitochondrial serine hydroxymethyltransferase SHMT2, which catalyzes the rate-limiting step in serine catabolism, drives cancer cell proliferation, but how this role is regulated is undefined. Here, we report that the sirtuin SIRT5 desuccinylates SHMT2 to increase its activity and drive serine catabolism in tumor cells. SIRT5 interaction directly mediated desuccinylation of lysine 280 on SHMT2, which was crucial for activating its enzymatic activity. Conversely, hypersuccinylation of SHMT2 at lysine 280 was sufficient to inhibit its enzymatic activity and downregulate tumor cell growth in vitro and in vivo. Notably, SIRT5 inactivation led to SHMT2 enzymatic downregulation and to abrogated cell growth under metabolic stress. Our results reveal that SHMT2 desuccinylation is a pivotal signal in cancer cells to adapt serine metabolic processes for rapid growth, and they highlight SIRT5 as a candidate target for suppressing serine catabolism as a strategy to block tumor growth.Significance: These findings reveal a novel mechanism for controlling cancer cell proliferation by blocking serine catabolism, as a general strategy to impede tumor growth. Cancer Res; 78(2); 372-86.Ó2017 AACR.

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“…It has recently been suggested that the p53 tumor suppressor gene inhibits PHGDH expression and consequently the de novo SSP [15,16]. A study using a human colon cancer cell line already demonstrated that a lack of p53 induced failure in dealing with serine starvation, proceeding to oxidative stress and impaired proliferation.…”

Section: Discussionmentioning

confidence: 99%

Clinical Implication of Serine Metabolism-Associated Enzymes in Colon Cancer

Yoon

Kim

Seo³

et al. 2015

Oncology

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Purpose: Recently, enzymes of the serine synthetic pathway (SSP) have been suggested as key player in the metabolic adaptation of oncogenesis. We assessed the expression of enzymes of the SSP in colonic tumor tissue (TT) and paired normal tissue (pNT) and the prognostic implications. Methods: From 2006 to 2010, we included 486 patients with colon cancer who underwent curative surgery at Kyungpook National University Hospital. Phosphoglycerate dehydrogenase (PHGDH), pyruvate dehydrogenase kinase (PDK) 1, PDK2, pyruvate kinase M2 (PKM2), and phosphoserine aminotransferase (PSAT) expression were investigated by immunohistochemical staining (IHC) in TT and pNT. The IHC values were calculated by multiplying intensity by proportion. The final score was classified as follows: 0-2 as negative and 3-12 as positive. Results: During the median follow-up duration of 55.5 months (37.4-90.6), 78 patients experienced recurrence. The expression of PHGDH, PDK1, and PSAT was significantly higher in TT than pNT (p < 0.001 for each). The univariate analysis for relapse-free survival revealed that TT PDK2 positivity was the only positive prognostic factor (p = 0.023). However, the expression of TT PDK2 did not represent a prognostic value in multivariate analysis. Conclusions: In conclusion, PHGDH, PDK1, and PSAT were significantly increased in colonic TT compared with pNT. The prognostic implication of these enzymes needs to be further investigated.

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p53 Protein-mediated Regulation of Phosphoglycerate Dehydrogenase (PHGDH) Is Crucial for the Apoptotic Response upon Serine Starvation

Cited by 110 publications

References 37 publications

Activation of SAT1 engages polyamine metabolism with p53-mediated ferroptotic responses

Activation of SAT1 engages polyamine metabolism with p53-mediated ferroptotic responses

SHMT2 Desuccinylation by SIRT5 Drives Cancer Cell Proliferation

Clinical Implication of Serine Metabolism-Associated Enzymes in Colon Cancer

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