PRAME expression in melanoma is negatively regulated by TET2-mediated DNA hydroxymethylation.

Autor:	Fang R; Department of Medicine, Brigham and Women's Hospital; Harvard Medical School, Boston MA 02115., Vallius T; Laboratory of Systems Pharmacology, Harvard Medical School, Boston MA 02115 Laboratory of Systems Pharmacology, Harvard Program in Therapeutic Science, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115.; Ludwig Cancer Center at Harvard, Boston, MA 02115., Zhang A; Department of Dermatology, Brigham and Women's Hospital; Harvard Medical School, Boston MA 02115., Van Cura D; Department of Chemistry and Chemical Biology, Harvard University, Cambridge MA 02138., Alicandri F; Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston MA 02115., Fischer G; Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston MA 02115., Draper E; Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston MA 02115., Xu S; Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston MA 02115., Pelletier R; Laboratory of Systems Pharmacology, Harvard Medical School, Boston MA 02115 Laboratory of Systems Pharmacology, Harvard Program in Therapeutic Science, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115.; Ludwig Cancer Center at Harvard, Boston, MA 02115., Katsyv I; Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston MA 02115., Sorger PK; Laboratory of Systems Pharmacology, Harvard Medical School, Boston MA 02115 Laboratory of Systems Pharmacology, Harvard Program in Therapeutic Science, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115.; Ludwig Cancer Center at Harvard, Boston, MA 02115.; Department of Systems Biology, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115., Murphy GF; Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston MA 02115., Lian CG; Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston MA 02115.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2024 Jul 26. Date of Electronic Publication: 2024 Jul 26.
DOI:	10.1101/2024.07.26.605293
Abstrakt:	Preferentially Expressed Antigen in Melanoma (PRAME) and Ten-Eleven Translocation (TET) dioxygenase-mediated 5-hydroxymethylcytosine (5hmC) are emerging melanoma biomarkers. We observed an inverse correlation between PRAME expression and 5hmC levels in benign nevi, melanoma in situ, primary invasive melanoma, and metastatic melanomas via immunohistochemistry and multiplex immunofluorescence: nevi exhibited high 5hmC and low PRAME, whereas melanomas showed the opposite pattern. Single-cell multiplex imaging of melanoma precursors revealed that diminished 5hmC coincides with PRAME upregulation in premalignant cells. Analysis of TCGA and GTEx databases confirmed a negative relationship between TET2 and PRAME mRNA expression in melanoma. Additionally, 5hmC levels were reduced at the PRAME 5' promoter in melanoma compared to nevi, suggesting a role for 5hmC in PRAME transcription. Restoring 5hmC levels via TET2 overexpression notably reduced PRAME expression in melanoma cell lines. These findings establish a function of TET2-mediated DNA hydroxymethylation in regulating PRAME expression and demonstrate epigenetic reprogramming as pivotal in melanoma tumorigenesis. Teaser: Melanoma biomarker PRAME expression is negatively regulated epigenetically by TET2-mediated DNA hydroxymethylation.
Databáze:	MEDLINE
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