TET2 Negatively Regulates Nestin Expression in Human Melanoma.
Although melanoma is an aggressive cancer, the understanding of the virulence-conferring pathways involved remains incomplete. We have demonstrated that loss of ten-eleven translocation methylcytosine dioxygenase (TET2)-mediated 5-hydroxymethylcytosine (5-hmC) is an epigenetic driver of melanoma growth and a biomarker of clinical virulence. We also have determined that the intermediate filament protein nestin correlates with tumorigenic and invasive melanoma growth. Here we examine the relationships between these two biomarkers. Immunohistochemistry staining of nestin and 5-hmC in 53 clinically annotated primary and metastatic patient melanomas revealed a significant negative correlation. Restoration of 5-hmC, as assessed in a human melanoma cell line by introducing full-length TET2 and TET2-mutated constructs, decreased nestin gene and protein expression in vitro. Genome-wide mapping using hydroxymethylated DNA immunoprecipitation sequencing disclosed significantly less 5-hmC binding in the 3' untranslated region of the nestin gene in melanoma compared to nevi, and 5-hmC binding in this region was significantly increased after TET2 overexpression in human melanoma cells in vitro. Our findings provide evidence suggesting that nestin regulation is negatively controlled epigenetically by TET2 via 5-hmC binding at the 3' untranslated region of the nestin gene, providing one potential pathway for understanding melanoma growth characteristics. Studies are now indicated to further define the interplay between 5-hmC, nestin expression, and melanoma virulence.
Program in Oral Pathology, Department of Oral Diagnosis, School of Dentistry, University of Campinas, Piracicaba, Brazil; Program in Dermatopathology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
Camilla B F
CB
Gomes
Program in Oral Pathology, Department of Oral Diagnosis, School of Dentistry, University of Campinas, Piracicaba, Brazil.
Karina G
KG
Zechin
Program in Dermatopathology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
Shuyun
S
Xu
Department of Pathology, Medical Sciences School, University of Campinas, Piracicaba, Brazil.
Rafael F
RF
Stelini
Department of Head and Surgery and Otorhinolaryngology, A.C. Camargo Cancer Center, São Paulo, Brazil.
Ines N
IN
Nishimoto
Program in Dermatopathology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
Qian
Q
Zhan
Program in Dermatopathology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
Ting
T
Xu
Program in Dermatopathology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
Gungwei
G
Qin
Division of Oral Medicine and Dentistry, Brigham and Women's Hospital, Harvard School of Dental Medicine, Boston, Massachusetts.
Nathaniel S
NS
Treister
Program in Dermatopathology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts. Electronic address: gmurphy@rics.bwh.harvard.edu.
George F
GF
Murphy
Program in Dermatopathology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts. Electronic address: cglian@bwh.harvard.edu.
Christine G
CG
Lian
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000032:analysis; D004268:DNA-Binding Proteins / Q000378:metabolism*; D049308:Dioxygenases; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D008297:Male; D008545:Melanoma / Q000378:metabolism*; D008875:Middle Aged; D064231:Nestin / Q000096:biosynthesis*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D012878:Skin Neoplasms; D046888:Tissue Array Analysis; D000096142:Cutaneous Malignant Melanoma
D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; C577484:NES protein, human; D064231:Nestin; D011518:Proto-Oncogene Proteins; D049308:Dioxygenases; C541081:TET2 protein, human