PSPH promotes melanoma growth and metastasis by metabolic deregulation-mediated transcriptional activation of NR4A1
Open accessAbstract
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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PSPH is a promising prognostic biomarker in different cancers such as advanced colorectal cancer, thyroid cancer, and melanoma.
“PSPH is associated with the development of various cancers and is a promising prognostic biomarker in different cancers such as advanced colorectal cancer [17], thyroid cancer [18] and melanoma [19].”
From Phosphoserine phosphatase as a prognostic biomarker in patients with gastric cancer and its potential association with immune cells (2022) · cites this paper as [19]
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“PSP knockdown tumour cells showed an increase in 2-hydroxyglutarate level 18 , which inhibits the TET family of DNA demethylases and the Jumonji family of histone demethylase, which impact on gene expression.”
[Nur77 promotes invasion and migration of gastric cancer cells through the NF-κB/IL-6 pathway].
Li, W., Shi, Y., Guo, Y., & Tian, S. (2022) · PubMed Central · doi:10.12122/j.issn.1673-4254.2022.09.19 · Cited by 2 · see citing works
The serine synthesis pathway is indispensable for glioblastoma growth and malignancy
Yun, H. J., Liu, R. R., & Lee, J. (2025) · Biotechnology and Bioprocess Engineering · doi:10.1007/s12257-025-00247-1 · Cited by 1 · see citing works
PROTAC-based protein degradation: a window of opportunity for melanoma therapy
Gentile, G., D’Aguanno, S., Martile, M. D., Petricca, A., Valentini, E., Scalera, S., & Bufalo, D. D. (2026) · Journal of Biomedical Science · doi:10.1186/s12929-026-01225-2 · Cited by 1 · see citing works
“Extensive preclinical studies have underscored a pro-tumorigenic role of NR4A1 through its “non-genomic” effect [138] on fatty acid oxidation [139] , apoptosis [140] , autophagy [141], angiogenesis [142], metastatization [143, 144] and immune system [145] .”
Lin, Q., Ji, Y., Yang, B., Zhu, R., Song, P., & Zhao, R. C. (2026) · Stem Cell Research & Therapy · doi:10.1186/s13287-026-04964-z · Cited by 1 · see citing works
“PSPH, an enzyme involved in the serine metabolism pathway, has been implicated in cancer progression and survival [21].”
Lentiviral mediated overexpression of NR4A1 in mononuclear cells ameliorates lupus nephritis
Zhang, Y., Linghua, Z., & Jing, H. (2021)
Single‐cell RNA sequencing reveals blastomere heterogeneity of 2‐cell embryos in pigs
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Self-citationHuang, M.-Y., Liu, X.-Y., Shao, Q., Zhang, X., Miao, L., Wu, X.-Y., Xu, Y.-X., Wang, F., Wang, H.-Y., Zeng, L., et al. (2022) · Figshare · doi:10.6084/m9.figshare.17799222
Self-citationTargeting one-carbon metabolic vulnerabilities of metastasis with therapeutic potentialPreprint
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“As a critical source of one-carbon units, serine is involved in the regulation of various tumor cells and T lymphocytes (41 – 44), and has been primarily studied in tumor cells (45, 46).”
IGF2BP2-driven serine metabolism promotes the progression of thyroid carcinoma via m6A-PHGDH
zhang, Y., Xiao, Z., Dong, X., & Wang, Q. Z. A. G. (2026) · Journal of Translational Medicine · doi:10.1186/s12967-026-08316-6
“Additionally, high PSPH expression is related to a poor prognosis of liver cancer [48], and it can promote the growth and metastasis of melanoma [49].”
Yi, Y., Min, H., Huang, Y., Tao, L., Zhou, H., Zhang, W., Ren, X., Huang, C., Deng, Y., & Zhou, J. (2026) · Current Issues in Molecular Biology · doi:10.3390/cimb48080784
- Authors
- Rawat, V., Malvi, P., Della Manna, D., Yang, E. S., Bugide, S., Zhang, X., Gupta, R., & Wajapeyee, N.
- Affiliations
- University of Alabama at Birmingham (US)
- Yale University (US)
- Corresponding author
- Wajapeyee, Narendra
- ORCID
- Venue
- Oncogene
- Published
- 2021-03-05
- Volume
- 40
- Issue
- 13
- Pages
- 2448-2462
- ISSN
- 0950-9232 (ISSN-L)
- 1476-5594
- PMC
- PMC8026604
- OpenAlex
- W3133570421
- Cited by
- 43
- References
- 49
- Citations by year
- 2026: 7 · 2025: 9 · 2024: 8 · 2023: 9 · 2022: 8 · 2021: 2
- FWCI
- 2.78
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Oncogene (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- U.S. Department of Health & Human Services | National Institutes of Health
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Keywords
- phosphoserine phosphatase, melanoma, metastasis, serine metabolism, 2-hydroxyglutarate, DNA demethylation, histone demethylation, 5-hydroxymethylcytosine, H3K4me3, Nur77, transcriptional activation, metabolic deregulation, tumor growth
- MeSH terms
- Animals, Glutarates, Humans, Melanoma, Neoplasm Metastasis, Phosphoric Monoester Hydrolases, RNA, Messenger, Serine, Transcriptional Activation, Gene Expression Regulation, Neoplastic, Cell Line, Tumor, Cell Proliferation, Mice, Gene Knockdown Techniques, Histone Demethylases, Jumonji Domain-Containing Histone Demethylases, Nuclear Receptor Subfamily 4, Group A, Member 1, Heterografts
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