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PSPH promotes melanoma growth and metastasis by metabolic deregulation-mediated transcriptional activation of NR4A1

Oncogene volume 40, pages 2448–2462 (2021)Cite this article

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Abstract

Metabolic deregulation, a hallmark of cancer, fuels cancer cell growth and metastasis. Here, we show that phosphoserine phosphatase (PSPH), an enzyme of the serine metabolism pathway, is upregulated in patient-derived melanoma samples. PSPH knockdown using short hairpin RNAs (shRNAs) blocks melanoma tumor growth and metastasis in both cell culture and mice. To elucidate the mechanism underlying PSPH action, we evaluated PSPH shRNA-expressing melanoma cells using global metabolomics and targeted mRNA expression profiling. Metabolomics analysis showed an increase in 2-hydroxyglutarate (2-HG) levels in PSPH knockdown cells. 2-HG inhibits the TET family of DNA demethylases and the Jumonji family of histone demethylases (KDM and JMJD), which is known to impact gene expression. Consistent with these data, PSPH knockdown in melanoma cells showed reduced DNA 5-hydroxymethylcytosine (5hmC) and increased histone H3K4me3 modifications. 2-HG treatment also inhibited melanoma growth. The nCounter PanCancer Pathways Panel-based mRNA expression profiling revealed attenuation of a number of cancer-promoting pathways upon PSPH knockdown. In particular, PSPH was necessary for nuclear receptor NR4A1 expression. Ectopic NR4A1 expression partly rescued the growth of melanoma cells expressing PSPH shRNA. Collectively, these results link PSPH to the facilitation of melanoma growth and metastasis through suppression of 2-HG and thus activation of pro-oncogenic gene expression.

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Fig. 1: PSPH is overexpressed in melanoma.
Fig. 2: PSPH is necessary for melanoma tumor growth and metastasis.
Fig. 3: PSPH loss results in widespread changes in metabolic pathways.
Fig. 4: PSPH loss causes global changes in metabolic pathways.
Fig. 5: PSPH loss results in the inhibition of H3K4me3 and 5hmC marks.
Fig. 6: PSPH loss results in reduced expression of cancer-promoting pathways and gene signatures.
Fig. 7: Ectopic expression of NR4A1 partially rescues PSPH knockdown-induced inhibition of melanoma growth.
Fig. 8: Model.

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References

  1. Chin L, Garraway LA, Fisher DE. Malignant melanoma: genetics and therapeutics in the genomic era. Genes Dev. 2006;20:2149–82.

    Article  CAS  PubMed  Google Scholar 

  2. Tsao H, Chin L, Garraway LA, Fisher DE. Melanoma: from mutations to medicine. Genes Dev. 2012;26:1131–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Cancer Genome Atlas Network. Genomic classification of cutaneous melanoma. Cell. 2015;161:1681–96.

    Article  Google Scholar 

  4. Larkin J, Ascierto PA, Dreno B, Atkinson V, Liszkay G, Maio M, et al. Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N. Engl J Med. 2014;371:1867–76.

    Article  PubMed  Google Scholar 

  5. Long GV, Stroyakovskiy D, Gogas H, Levchenko E, de Braud F, Larkin J, et al. Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma. N. Engl J Med. 2014;371:1877–88.

    Article  PubMed  Google Scholar 

  6. Kakadia S, Yarlagadda N, Awad R, Kundranda M, Niu J, Naraev B, et al. Mechanisms of resistance to BRAF and MEK inhibitors and clinical update of US Food and Drug Administration-approved targeted therapy in advanced melanoma. Onco Targets Ther. 2018;11:7095–107.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Luke JJ, Flaherty KT, Ribas A, Long GV. Targeted agents and immunotherapies: optimizing outcomes in melanoma. Nat Rev Clin Oncol. 2017;14:463–82.

    Article  CAS  PubMed  Google Scholar 

  8. Nowicki TS, Hu-Lieskovan S, Ribas A. Mechanisms of resistance to PD-1 and PD-L1 blockade. Cancer J. 2018;24:47–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Warburg O, Wind F, Negelein E. The metabolism of tumors in the body. J Gen Physiol. 1927;8:519–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Fischer GM, Vashisht Gopal YN, McQuade JL, Peng W, DeBerardinis RJ, Davies MA. Metabolic strategies of melanoma cells: mechanisms, interactions with the tumor microenvironment, and therapeutic implications. Pigment Cell Melanoma Res. 2018;31:11–30.

    Article  PubMed  Google Scholar 

  11. Ratnikov BI, Scott DA, Osterman AL, Smith JW, Ronai ZA. Metabolic rewiring in melanoma. Oncogene. 2017;36:147–57.

    Article  CAS  PubMed  Google Scholar 

  12. Amelio I, Cutruzzola F, Antonov A, Agostini M, Melino G. Serine and glycine metabolism in cancer. Trends Biochem Sci. 2014;39:191–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Yang M, Vousden KH. Serine and one-carbon metabolism in cancer. Nat Rev Cancer. 2016;16:650–62.

    Article  CAS  PubMed  Google Scholar 

  14. Fan J, Teng X, Liu L, Mattaini KR, Looper RE, Vander Heiden MG, et al. Human phosphoglycerate dehydrogenase produces the oncometabolite D-2-hydroxyglutarate. ACS Chem Biol. 2015;10:510–6.

    Article  CAS  PubMed  Google Scholar 

  15. Sullivan MR, Mattaini KR, Dennstedt EA, Nguyen AA, Sivanand S, Reilly MF, et al. Increased serine synthesis provides an advantage for tumors arising in tissues where serine levels are limiting. Cell Metab. 2019;29:1410–1421. e1414.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Beroukhim R, Mermel CH, Porter D, Wei G, Raychaudhuri S, Donovan J, et al. The landscape of somatic copy-number alteration across human cancers. Nature. 2010;463:899–905.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Mullarky E, Mattaini KR, Vander Heiden MG, Cantley LC, Locasale JW. PHGDH amplification and altered glucose metabolism in human melanoma. Pigment Cell Melanoma Res. 2011;24:1112–5.

    Article  CAS  PubMed  Google Scholar 

  18. Locasale JW, Grassian AR, Melman T, Lyssiotis CA, Mattaini KR, Bass AJ, et al. Phosphoglycerate dehydrogenase diverts glycolytic flux and contributes to oncogenesis. Nat Genet. 2011;43:869–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Gao S, Ge A, Xu S, You Z, Ning S, Zhao Y, et al. PSAT1 is regulated by ATF4 and enhances cell proliferation via the GSK3beta/beta-catenin/cyclin D1 signaling pathway in ER-negative breast cancer. J Exp Clin Cancer Res. 2017;36:179.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Jin HO, Hong SE, Kim JY, Jang SK, Kim YS, Sim JH, et al. Knock-down of PSAT1 enhances sensitivity of NSCLC cells to glutamine-limiting conditions. Anticancer Res. 2019;39:6723–30.

    Article  CAS  PubMed  Google Scholar 

  21. Liao L, Ge M, Zhan Q, Huang R, Ji X, Liang X, et al. PSPH mediates the metastasis and proliferation of non-small cell lung cancer through MAPK signaling pathways. Int J Biol Sci. 2019;15:183–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Park SM, Seo EH, Bae DH, Kim SS, Kim J, Lin W, et al. Phosphoserine phosphatase promotes lung cancer progression through the dephosphorylation of IRS-1 and a noncanonical L-serine-independent pathway. Mol Cells. 2019;42:604–16.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Kampen KR, Fancello L, Girardi T, Rinaldi G, Planque M, Sulima SO, et al. Translatome analysis reveals altered serine and glycine metabolism in T-cell acute lymphoblastic leukemia cells. Nat Commun. 2019;10:2542.

    Article  PubMed  PubMed Central  Google Scholar 

  24. McCabe A, Dolled-Filhart M, Camp RL, Rimm DL. Automated quantitative analysis (AQUA) of in situ protein expression, antibody concentration, and prognosis. J Natl Cancer Inst. 2005;97:1808–15.

    Article  CAS  PubMed  Google Scholar 

  25. van Zijl F, Krupitza G, Mikulits W. Initial steps of metastasis: cell invasion and endothelial transmigration. Mutat Res. 2011;728:23–34.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Pacold ME, Brimacombe KR, Chan SH, Rohde JM, Lewis CA, Swier LJ, et al. A PHGDH inhibitor reveals coordination of serine synthesis and one-carbon unit fate. Nat Chem Biol. 2016;12:452–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Hausinger RP. FeII/alpha-ketoglutarate-dependent hydroxylases and related enzymes. Crit Rev Biochem Mol Biol. 2004;39:21–68.

    Article  CAS  PubMed  Google Scholar 

  28. Li S, Swanson SK, Gogol M, Florens L, Washburn MP, Workman JL, et al. Serine and SAM responsive complex SESAME regulates histone modification crosstalk by sensing cellular metabolism. Mol Cell. 2015;60:408–21.

    Article  CAS  PubMed  Google Scholar 

  29. Xu W, Yang H, Liu Y, Yang Y, Wang P, Kim SH, et al. Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of alpha-ketoglutarate-dependent dioxygenases. Cancer Cell. 2011;19:17–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Ye D, Guan KL, Xiong Y. Metabolism, activity, and targeting of D- and L-2-hydroxyglutarates. Trends Cancer. 2018;4:151–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Su R, Dong L, Li C, Nachtergaele S, Wunderlich M, Qing Y, et al. R-2HG exhibits anti-tumor activity by targeting FTO/m(6)A/MYC/CEBPA signaling. Cell. 2018;172:90–105. e123.

    Article  CAS  PubMed  Google Scholar 

  32. Zhan YY, Chen Y, Zhang Q, Zhuang JJ, Tian M, Chen HZ, et al. The orphan nuclear receptor Nur77 regulates LKB1 localization and activates AMPK. Nat Chem Biol. 2012;8:897–904.

    Article  CAS  PubMed  Google Scholar 

  33. Li XX, Wang ZJ, Zheng Y, Guan YF, Yang PB, Chen X, et al. Nuclear receptor Nur77 facilitates melanoma cell survival under metabolic stress by protecting fatty acid oxidation. Mol Cell. 2018;69:480–492. e487.

    Article  CAS  PubMed  Google Scholar 

  34. DiNardo CD, Stein EM, de Botton S, Roboz GJ, Altman JK, Mims AS, et al. Durable remissions with ivosidenib in IDH1-mutated relapsed or refractory AML. N. Engl J Med. 2018;378:2386–98.

    Article  CAS  PubMed  Google Scholar 

  35. Cao L, Weetall M, Trotta C, Cintron K, Ma J, Kim MJ, et al. Targeting of hematologic malignancies with PTC299, a novel potent inhibitor of dihydroorotate dehydrogenase with favorable pharmaceutical properties. Mol Cancer Ther. 2019;18:3–16.

    Article  CAS  PubMed  Google Scholar 

  36. Mattaini KR, Sullivan MR, Vander, Heiden MG. The importance of serine metabolism in cancer. J Cell Biol. 2016;214:249–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Koo JS, Yoon JS. Expression of metabolism-related proteins in lacrimal gland adenoid cystic carcinoma. Am J Clin Pathol. 2015;143:584–92.

    Article  PubMed  Google Scholar 

  38. Tan EH, Ramlau R, Pluzanska A, Kuo HP, Reck M, Milanowski J, et al. A multicentre phase II gene expression profiling study of putative relationships between tumour biomarkers and clinical response with erlotinib in non-small-cell lung cancer. Ann Oncol. 2010;21:217–22.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Zhang B, Zheng A, Hydbring P, Ambroise G, Ouchida AT, Goiny M, et al. PHGDH defines a metabolic subtype in lung adenocarcinomas with poor prognosis. Cell Rep. 2017;19:2289–303.

    Article  CAS  PubMed  Google Scholar 

  40. Song Z, Feng C, Lu Y, Lin Y, Dong C. PHGDH is an independent prognosis marker and contributes cell proliferation, migration and invasion in human pancreatic cancer. Gene. 2018;642:43–50.

    Article  CAS  PubMed  Google Scholar 

  41. Wang CY, Chiao CC, Phan NN, Li CY, Sun ZD, Jiang JZ, et al. Gene signatures and potential therapeutic targets of amino acid metabolism in estrogen receptor-positive breast cancer. Am J Cancer Res. 2020;10:95–113.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Sato K, Masuda T, Hu Q, Tobo T, Kidogami S, Ogawa Y, et al. Phosphoserine phosphatase is a novel prognostic biomarker on chromosome 7 in colorectal cancer. Anticancer Res. 2017;37:2365–71.

    Article  CAS  PubMed  Google Scholar 

  43. Bachelor MA, Lu Y, Owens DM. L-3-Phosphoserine phosphatase (PSPH) regulates cutaneous squamous cell carcinoma proliferation independent of L-serine biosynthesis. J Dermatol Sci. 2011;63:164–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Chen J, Chung F, Yang G, Pu M, Gao H, Jiang W, et al. Phosphoglycerate dehydrogenase is dispensable for breast tumor maintenance and growth. Oncotarget. 2013;4:2502–11.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Possemato R, Marks KM, Shaul YD, Pacold ME, Kim D, Birsoy K, et al. Functional genomics reveal that the serine synthesis pathway is essential in breast cancer. Nature. 2011;476:346–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Locasale JW. Serine, glycine and one-carbon units: cancer metabolism in full circle. Nat Rev Cancer. 2013;13:572–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Chowdhury R, Yeoh KK, Tian YM, Hillringhaus L, Bagg EA, Rose NR, et al. The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases. EMBO Rep. 2011;12:463–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Zhao G, Winkler ME. A novel alpha-ketoglutarate reductase activity of the serA-encoded 3-phosphoglycerate dehydrogenase of Escherichia coli K-12 and its possible implications for human 2-hydroxyglutaric aciduria. J Bacteriol. 1996;178:232–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Hazel TG, Nathans D, Lau LF. A gene inducible by serum growth factors encodes a member of the steroid and thyroid hormone receptor superfamily. Proc Natl Acad Sci USA. 1988;85:8444–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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  1. These authors contributed equally: Vipin Rawat, Parmanand Malvi

Authors and Affiliations

  1. Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, AL, USA

    Vipin Rawat, Parmanand Malvi, Suresh Bugide, Romi Gupta & Narendra Wajapeyee

  2. Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, AL, USA

    Deborah Della Manna & Eddy S. Yang

  3. Department of Pathology, Yale University School of Medicine, New Haven, CT, USA

    Xuchen Zhang

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Rawat, V., Malvi, P., Della Manna, D. et al. PSPH promotes melanoma growth and metastasis by metabolic deregulation-mediated transcriptional activation of NR4A1. Oncogene 40, 2448–2462 (2021). https://doi.org/10.1038/s41388-021-01683-y

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