Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
BMC Cancer
Published in: BMC Cancer 1/2019

Open Access 01-12-2019 | Doxycycline | Research article

Increased PHGDH expression promotes aberrant melanin accumulation

Authors: Katherine R. Mattaini, Mark R. Sullivan, Allison N. Lau, Brian P. Fiske, Roderick T. Bronson, Matthew G. Vander Heiden

Published in: BMC Cancer | Issue 1/2019

Login to get access

Abstract

Background

Copy number gain of the D-3-phosphoglycerate dehydrogenase (PHGDH) gene, which encodes the first enzyme in serine biosynthesis, is found in some human cancers including a subset of melanomas.

Methods

In order to study the effect of increased PHGDH expression in tissues in vivo, we generated mice harboring a PHGDHtetO allele that allows tissue-specific, doxycycline-inducible PHGDH expression, and we analyzed the phenotype of mice with a ubiquitous increase in PHGDH expression.

Results

Tissues and cells derived from PHGDHtetO mice exhibit increased serine biosynthesis. Histological examination of skin tissue from PHGDHtetO mice reveals the presence of melanin granules in early anagen hair follicles, despite the fact that melanin synthesis is closely coupled to the hair follicle cycle and does not normally begin until later in the cycle. This phenotype occurs in the absence of any global change in hair follicle cycle timing. The aberrant presence of melanin early in the hair follicle cycle following PHGDH expression is also accompanied by increased melanocyte abundance in early anagen skin.

Conclusions

These data suggest increased PHGDH expression impacts normal melanocyte biology, but PHGDH expression alone is not sufficient to cause cancer.
Appendix
Available only for authorised users
Literature
1.
Locasale JW, Grassian AR, Melman T, Lyssiotis CA, Mattaini KR, Bass AJ, Heffron G, Metallo CM, Muranen T, Sharfi H, et al. Phosphoglycerate dehydrogenase diverts glycolytic flux and contributes to oncogenesis. Nat Genet. 2011;43(9):869–74.CrossRef
2.
Possemato R, Marks KM, Shaul YD, Pacold ME, Kim D, Birsoy K, Sethumadhavan S, Woo HK, Jang HG, Jha AK, et al. Functional genomics reveal that the serine synthesis pathway is essential in breast cancer. Nature. 2011;476(7360):346–50.CrossRef
3.
Mattaini KR, Brignole EJ, Kini M, Davidson SM, Fiske BP, Drennan CL, Vander Heiden MG. An epitope tag alters phosphoglycerate dehydrogenase structure and impairs ability to support cell proliferation. Cancer Metab. 2015;3:5.CrossRef
4.
Pollari S, Kakonen SM, Edgren H, Wolf M, Kohonen P, Sara H, Guise T, Nees M, Kallioniemi O. Enhanced serine production by bone metastatic breast cancer cells stimulates osteoclastogenesis. Breast Cancer Res Treat. 2011;125(2):421–30.CrossRef
5.
Liu J, Guo S, Li Q, Yang L, Xia Z, Zhang L, Huang Z, Zhang N. Phosphoglycerate dehydrogenase induces glioma cells proliferation and invasion by stabilizing forkhead box M1. J Neuro-Oncol. 2013;111(3):245–55.CrossRef
6.
Jing Z, Heng W, Aiping D, Yafei Q, Shulan Z. Expression and clinical significance of phosphoglycerate dehydrogenase and squamous cell carcinoma antigen in cervical cancer. Int J Gynecol Cancer. 2013;23(8):1465–9.CrossRef
7.
Zhu J, Ma J, Wang X, Ma T, Zhang S, Wang W, Zhou X, Shi J. High expression of PHGDH predicts poor prognosis in non-small cell lung Cancer. Transl Oncol. 2016;9(6):592–9.CrossRef
8.
Jia XQ, Zhang S, Zhu HJ, Wang W, Zhu JH, Wang XD, Qiang JF. Increased expression of PHGDH and prognostic significance in colorectal Cancer. Transl Oncol. 2016;9(3):191–6.CrossRef
9.
Nilsson LM, Forshell TZ, Rimpi S, Kreutzer C, Pretsch W, Bornkamm GW, Nilsson JA. Mouse genetics suggests cell-context dependency for Myc-regulated metabolic enzymes during tumorigenesis. PLoS Genet. 2012;8(3):e1002573.CrossRef
10.
Adams CM. Role of the transcription factor ATF4 in the anabolic actions of insulin and the anti-anabolic actions of glucocorticoids. J Biol Chem. 2007;282(23):16744–53.CrossRef
11.
Ding J, Li T, Wang X, Zhao E, Choi JH, Yang L, Zha Y, Dong Z, Huang S, Asara JM, et al. The histone H3 methyltransferase G9A epigenetically activates the serine-glycine synthesis pathway to sustain cancer cell survival and proliferation. Cell Metab. 2013;18(6):896–907.CrossRef
12.
Sullivan MR, Mattaini KR, Dennstedt EA, Nguyen AA, Sivanand S, Reilly MF, Meeth K, Muir A, Darnell AM, Bosenberg MW, et al. Increased serine synthesis provides an advantage for tumors arising in tissues where serine levels are limiting. Cell Metab. 2019;29(6):1410–1421 e1414.CrossRef
13.
Ou Y, Wang SJ, Jiang L, Zheng B, Gu W. p53 protein-mediated regulation of phosphoglycerate dehydrogenase (PHGDH) is crucial for the apoptotic response upon serine starvation. J Biol Chem. 2015;290(1):457–66.CrossRef
14.
15.
Fuchs E. Scratching the surface of skin development. Nature. 2007;445(7130):834–42.CrossRef
16.
Cotsarelis G, Sun TT, Lavker RM. Label-retaining cells reside in the bulge area of pilosebaceous unit: implications for follicular stem cells, hair cycle, and skin carcinogenesis. Cell. 1990;61(7):1329–37.CrossRef
17.
Nishimura EK, Jordan SA, Oshima H, Yoshida H, Osawa M, Moriyama M, Jackson IJ, Barrandon Y, Miyachi Y, Nishikawa S. Dominant role of the niche in melanocyte stem-cell fate determination. Nature. 2002;416(6883):854–60.CrossRef
18.
Slominski A, Paus R. Melanogenesis is coupled to murine anagen: toward new concepts for the role of melanocytes and the regulation of melanogenesis in hair growth. J Invest Dermatol. 1993;101(1 Suppl):90S–7S.CrossRef
19.
Muller-Rover S, Handjiski B, van der Veen C, Eichmuller S, Foitzik K, McKay IA, Stenn KS, Paus R. A comprehensive guide for the accurate classification of murine hair follicles in distinct hair cycle stages. J Invest Dermatol. 2001;117(1):3–15.CrossRef
20.
Hwang IY, Kwak S, Lee S, Kim H, Lee SE, Kim JH, Kim YA, Jeon YK, Chung DH, Jin X, et al. Psat1-dependent fluctuations in alpha-ketoglutarate affect the timing of ESC differentiation. Cell Metab. 2016;24(3):494–501.CrossRef
21.
Samanta D, Park Y, Andrabi SA, Shelton LM, Gilkes DM, Semenza GL. PHGDH expression is required for mitochondrial redox homeostasis, breast Cancer stem cell maintenance, and lung metastasis. Cancer Res. 2016;76(15):4430–42.CrossRef
22.
Beard C, Hochedlinger K, Plath K, Wutz A, Jaenisch R. Efficient method to generate single-copy transgenic mice by site-specific integration in embryonic stem cells. Genesis. 2006;44(1):23–8.CrossRef
23.
Zambrowicz BP, Imamoto A, Fiering S, Herzenberg LA, Kerr WG, Soriano P. Disruption of overlapping transcripts in the ROSA beta geo 26 gene trap strain leads to widespread expression of beta-galactosidase in mouse embryos and hematopoietic cells. Proc Natl Acad Sci U S A. 1997;94(8):3789–94.CrossRef
24.
Fedorov LM, Tyrsin OY, Krenn V, Chernigovskaya EV, Rapp UR. Tet-system for the regulation of gene expression during embryonic development. Transgenic Res. 2001;10(3):247–58.CrossRef
25.
Perl AK, Tichelaar JW, Whitsett JA. Conditional gene expression in the respiratory epithelium of the mouse. Transgenic Res. 2002;11(1):21–9.CrossRef
26.
Perl AK, Wert SE, Nagy A, Lobe CG, Whitsett JA. Early restriction of peripheral and proximal cell lineages during formation of the lung. Proc Natl Acad Sci U S A. 2002;99(16):10482–7.CrossRef
27.
Shin MK, Levorse JM, Ingram RS, Tilghman SM. The temporal requirement for endothelin receptor-B signalling during neural crest development. Nature. 1999;402(6761):496–501.CrossRef
28.
Davis JL, Fallon HJ. Studies on the role of 3-phosphoglycerate dehydrogenase in the regulation of serine biosynthesis in rat liver. J Biol Chem. 1970;245(21):5838–46.PubMed
29.
Tobin DJ, Hagen E, Botchkarev VA, Paus R. Do hair bulb melanocytes undergo apoptosis during hair follicle regression (catagen)? J Invest Dermatol. 1998;111(6):941–7.CrossRef
30.
Paus R, Foitzik K: In search of the "hair cycle clock": a guided tour. Differentiation 2004, 72(9–10):489–511.CrossRef
31.
Zaidi MR, Davis S, Noonan FP, Graff-Cherry C, Hawley TS, Walker RL, Feigenbaum L, Fuchs E, Lyakh L, Young HA, et al. Interferon-gamma links ultraviolet radiation to melanomagenesis in mice. Nature. 2011;469(7331):548–53.CrossRef
32.
Zaidi MR, Hornyak TJ, Merlino G. A genetically engineered mouse model with inducible GFP expression in melanocytes. Pigment Cell Melanoma Res. 2011;24(2):393–4.CrossRef
33.
Tumbar T, Guasch G, Greco V, Blanpain C, Lowry WE, Rendl M, Fuchs E. Defining the epithelial stem cell niche in skin. Science. 2004;303(5656):359–63.CrossRef
34.
Joshi SS, Tandukar B, Castaneda M, Jiang S, Diwakar G, Hertzano RP, Hornyak TJ. Characterization of a new, inducible transgenic mouse model with GFP expression in melanocytes and their precursors. Gene Expr Patterns. 2017;27:76–84.CrossRef
35.
Tobin DJ. Human hair pigmentation--biological aspects. Int J Cosmet Sci. 2008;30(4):233–57.CrossRef
36.
Schiaffino MV. Signaling pathways in melanosome biogenesis and pathology. Int J Biochem Cell Biol. 2010;42(7):1094–104.CrossRef
37.
Videira IF, Moura DF, Magina S. Mechanisms regulating melanogenesis. An Bras Dermatol. 2013;88(1):76–83.CrossRef
38.
Wang N, Hebert DN. Tyrosinase maturation through the mammalian secretory pathway: bringing color to life. Pigment Cell Res. 2006;19(1):3–18.CrossRef
39.
Hsiao JJ, Fisher DE. The roles of microphthalmia-associated transcription factor and pigmentation in melanoma. Arch Biochem Biophys. 2014;563:28–34.CrossRef
40.
Schallreuter KU, Kothari S, Chavan B, Spencer JD. Regulation of melanogenesis--controversies and new concepts. Exp Dermatol. 2008;17(5):395–404.CrossRef
41.
Hearing VJ. Determination of melanin synthetic pathways. J Invest Dermatol. 2011;131(E1):E8–E11.CrossRef
42.
Piskounova E, Agathocleous M, Murphy MM, Hu Z, Huddlestun SE, Zhao Z, Leitch AM, Johnson TM, DeBerardinis RJ, Morrison SJ. Oxidative stress inhibits distant metastasis by human melanoma cells. Nature. 2015;527(7577):186–91.CrossRef
Metadata
Title
Increased PHGDH expression promotes aberrant melanin accumulation
Authors
Katherine R. Mattaini
Mark R. Sullivan
Allison N. Lau
Brian P. Fiske
Roderick T. Bronson
Matthew G. Vander Heiden
Publication date
01-12-2019
Publisher
BioMed Central
Keyword
Doxycycline
Published in
BMC Cancer / Issue 1/2019
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-019-5933-5

Other articles of this Issue 1/2019

BMC Cancer 1/2019 Go to the issue

Research article

Risk evaluation of splenic hilar or splenic artery lymph node metastasis and survival analysis for patients with proximal gastric cancer after curative gastrectomy: a retrospective study

Research article

Efficacy and safety of RGB-02, a pegfilgrastim biosimilar to prevent chemotherapy-induced neutropenia: results of a randomized, double-blind phase III clinical study vs. reference pegfilgrastim in patients with breast cancer receiving chemotherapy

Study protocol

Phase I/IIa study of concomitant radiotherapy with olaparib and temozolomide in unresectable or partially resectable glioblastoma: OLA-TMZ-RTE-01 trial protocol

Research article

Substantial batch effects in TCGA exome sequences undermine pan-cancer analysis of germline variants

Research article

Different prognostic implication of ypTNM stage and pTNM stage for gastric cancer: a propensity score-matched analysis

Research article

Androgen receptor mRNA expression is a predictor for recurrence-free survival in non-muscle invasive bladder cancer
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits