Regulation of 5-Hydroxymethylcytosine by TET2 Contributes to Squamous Cell Carcinoma Tumorigenesis.
Regulation of 5-Hydroxymethylcytosine by TET2 Contributes to Squamous Cell Carcinoma Tumorigenesis.
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DOI：
10.1016/j.jid.2021.09.026
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发表时间：
2022-05
影响因子：
6.5
通讯作者：
Ramsey, Matthew R.
中科院分区：
文献类型：
--
作者：
Boudra, Rafik;Woappi, Yvon;Wang, Diana;Xu, Shuyun;Wells, Michael;Schmults, Chrysalyne D.;Lian, Christine G.;Ramsey, Matthew R.
DNA甲基化是控制多种生理过程的关键调控事件，对基因转录有显著影响。甲基化胞嘧啶(5mC)可以被Tet家族的酶氧化成5-羟甲基胞嘧啶(5-HMC)，5-HMC是去甲基化循环中的关键中间体，在急性髓细胞白血病和黑色素瘤等恶性肿瘤中5-HMC水平降低。我们构建了一个人类皮肤鳞状细胞癌(鳞状细胞癌)肿瘤的组织微阵列，发现与邻近皮肤相比，5-HMC水平在全球范围内降低。利用小鼠K14-Creer系统，我们发现TET2的缺失促进了致癌物诱导的鳞状细胞癌，并与TP53的缺失协同作用，推动了上皮组织中的自发性鳞癌的发生。TET2缺失后5-HMC和基因表达的变化分析显示，5-HMC水平的局灶性变化和毛囊瞬时扩增细胞基因的增加，以及表皮分化基因的减少。这些结果证明了TET2在表皮谱系中的作用，与已报道的Tet酶在控制造血干细胞和ES细胞的谱系承诺中的作用一致，并确立了TET2作为鳞癌中骨肿瘤抑制因子的作用。
DNA methylation is a key regulatory event controlling a variety of physiological processes and can have dramatic effects on gene transcription. Methylated Cytosine (5mC) 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 (Squamous Cell Carcinoma) tumors and found a global reduction in 5-hmC levels compared to 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 following 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 demonstrate a role for TET2 in epidermal lineage specification, consistent with reported roles for TET enzymes in controlling lineage commitment in hematopoietic stem cells and ES cells and establish TET2 as a bone fide tumor suppressor in Squamous Cell Carcinoma.
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影响因子：
50.3
作者：
Kunimoto H;Meydan C;Nazir A;Whitfield J;Shank K;Rapaport F;Maher R;Pronier E;Meyer SC;Garrett-Bakelman FE;Tallman M;Melnick A;Levine RL;Shih AH
通讯作者：
Shih AH
影响因子：
10.9
作者：
Jambusaria-Pahlajani, Anokhi;Kanetsky, Peter A.;Schmults, Chrysalyne D.
通讯作者：
Schmults, Chrysalyne D.
影响因子：
13.8
作者：
Karia, Pritesh S.;Han, Jiali;Schmults, Chrysalyne D.
通讯作者：
Schmults, Chrysalyne D.
影响因子：
158.5
作者：
Delhommeau, Francois;Dupont, Sabrina;Bernard, Olivier A.
通讯作者：
Bernard, Olivier A.
影响因子：
11.8
作者：
Dawlaty, Meelad M.;Breiling, Achim;Thuc Le;Barrasa, M. Inmaculada;Raddatz, Guenter;Gao, Qing;Powell, Benjamin E.;Cheng, Albert W.;Faull, Kym F.;Lyko, Frank;Jaenisch, Rudolf
通讯作者：
Jaenisch, Rudolf