AID assists DNMT1 to attenuate BCL6 expression through DNA methylation in diffuse large B-cell lymphoma cell lines

Autor: Mingzhe Zheng, Junna Jiao, Woodvine Otieno Odhiambo, Zhuangwei Lv, Xiaozhuo Yu, Meng Yuan, Yunfeng Ma, Ping Zhang, Yanhong Ji, Hua Zhang, Yang Wang
Rok vydání: 2020
Předmět:
DNA (Cytosine-5-)-Methyltransferase 1
0301 basic medicine
Original article
Cancer Research
lcsh:RC254-282
Models
Biological
Proto-Oncogene Mas
Mice
03 medical and health sciences
0302 clinical medicine
Genes
Reporter
immune system diseases
Cell Line
Tumor
Cytidine Deaminase
hemic and lymphatic diseases
medicine
Activation-induced (cytidine) deaminase
Animals
Humans
Promoter Regions
Genetic
BCL6 repression
DNA methylation
biology
Gene Expression Regulation
Leukemic
Chemistry
DNA methyltransferase 1
Germinal center
Diffuse large B-cell lymphoma
Cytidine deaminase
Methylation
lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens
medicine.disease
BCL6
DNA-Binding Proteins
Disease Models
Animal
030104 developmental biology
030220 oncology & carcinogenesis
Proto-Oncogene Proteins c-bcl-6
Cancer research
DNMT1
biology.protein
Lymphoma
Large B-Cell
Diffuse
Activation-induced cytidine deaminase
Protein Binding
Zdroj: Neoplasia (New York, N.Y.)
Neoplasia: An International Journal for Oncology Research, Vol 22, Iss 3, Pp 142-153 (2020)
ISSN: 1476-5586
Popis: The BCL6 proto-oncogene encodes a transcriptional repressor, which is required for germinal centers (GCs) formation and lymphomagenesis. Previous studies have been reported that the constitutive expression of BCL6 leads to diffuse large B cell lymphoma (DLBCL) through activation-induced cytidine deaminase (AID) mediated chromosomal translocations and mutations. However, other DLBCLs (45%) without structural variants were characterized by abnormally high level of BCL6 expression through an unknown mechanism. Herein, we report that deficiency in AID or methyltransferase 1 (DNMT1) triggers high level of BCL6 expression. AID-DNMT1 complex binds to −0.4 kb −0 kb region of BCL6 promoter and contributes to generate BCL6 methylation which results in inhibition of BCL6 expression. The proteasome pathway inhibitor MG132 induces accumulation of AID and DNMT1, causes decreased BCL6 expression, and leads to cell apoptosis and tumor growth inhibition in DLBCL cell xenograft mice. These findings propose mechanistic insight into an alternative cofactor role of AID in assisting DNMT1 to maintain BCL6 methylation, thus suppress BCL6 transcription in DLBCL. This novel mechanism will provide a new drug selection in the therapeutic approach to DLBCL in the future. Keywords: Activation-induced cytidine deaminase, DNA methyltransferase 1, BCL6 repression, DNA methylation, Diffuse large B-cell lymphoma
Databáze: OpenAIRE
Externí odkaz: