Regulation of 5-Hydroxymethylcytosine by TET2 Contributes to Squamous Cell Carcinoma Tumorigenesis.
J Invest Dermatol
; 142(5): 1270-1279.e2, 2022 05.
Article
em En
| MEDLINE
| ID: mdl-34695415
ABSTRACT
DNA methylation is a key regulatory event controlling a variety of physiological processes and can have dramatic effects on gene transcription. Methylated cytosine (5-methylcytosine) can be oxidized by the TET family of enzymes to 5-hydroxymethylcytosine (5-hmC), a key intermediate in the demethylation cycle, and 5-hmC levels are reduced in malignancies such as acute myeloid leukemia and melanoma. We constructed a tissue microarray of human cutaneous squamous cell carcinoma tumors and found a global reduction in 5-hmC levels compared with that in the adjacent skin. Using a murine K14-CreER system, we have found that loss of Tet2 promotes carcinogen-induced squamous cell carcinoma and cooperates with loss of Tp53 to drive spontaneous squamous cell carcinoma tumors in epithelial tissues. Analysis of changes in 5-hmC and gene expression after loss of Tet2 in the epidermis revealed focal alterations in 5-hmC levels and an increase in hair follicle transient amplifying cell genes along with a reduction in epidermal differentiation genes. These results show a role for TET2 in epidermal lineage specification, consistent with reported roles for TET enzymes in controlling lineage commitment in hematopoietic stem cells and embryonic stem cells and establishing TET2 as a bone fide tumor suppressor in squamous cell carcinoma.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Neoplasias Cutâneas
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Carcinoma de Células Escamosas
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Dioxigenases
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Proteínas de Ligação a DNA
Limite:
Animals
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Humans
Idioma:
En
Revista:
J Invest Dermatol
Ano de publicação:
2022
Tipo de documento:
Article
País de afiliação:
Estados Unidos
País de publicação:
EEUU
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ESTADOS UNIDOS
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ESTADOS UNIDOS DA AMERICA
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EUA
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UNITED STATES
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UNITED STATES OF AMERICA
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US
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USA