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

Junna Jiao; Zhuangwei Lv; Ping Zhang; Yang Wang; Meng Yuan; Xiaozhuo Yu; Woodvine Otieno Odhiambo; Mingzhe Zheng; Hua Zhang; Yunfeng Ma; Yanhong Ji

Neoplasia: An International Journal for Oncology Research (Mar 2020)

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

Junna Jiao,
Zhuangwei Lv,
Ping Zhang,
Yang Wang,
Meng Yuan,
Xiaozhuo Yu,
Woodvine Otieno Odhiambo,
Mingzhe Zheng,
Hua Zhang,
Yunfeng Ma,
Yanhong Ji

Affiliations

Junna Jiao: Department of Pathogenic Biology and Immunology, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Centre, Xi’an, Shaanxi, China; Key Laboratory of Environment and Genes Related to Diseases (Xi’an Jiaotong University), Ministry of Education of China, Xi’an, Shaanxi, China
Zhuangwei Lv: Department of Pathogenic Biology and Immunology, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Centre, Xi’an, Shaanxi, China; Key Laboratory of Environment and Genes Related to Diseases (Xi’an Jiaotong University), Ministry of Education of China, Xi’an, Shaanxi, China
Ping Zhang: Department of Pathogenic Biology and Immunology, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Centre, Xi’an, Shaanxi, China; Key Laboratory of Environment and Genes Related to Diseases (Xi’an Jiaotong University), Ministry of Education of China, Xi’an, Shaanxi, China
Yang Wang: Department of Pathogenic Biology and Immunology, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Centre, Xi’an, Shaanxi, China; Key Laboratory of Environment and Genes Related to Diseases (Xi’an Jiaotong University), Ministry of Education of China, Xi’an, Shaanxi, China
Meng Yuan: Department of Pathogenic Biology and Immunology, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Centre, Xi’an, Shaanxi, China; Key Laboratory of Environment and Genes Related to Diseases (Xi’an Jiaotong University), Ministry of Education of China, Xi’an, Shaanxi, China
Xiaozhuo Yu: Department of Pathogenic Biology and Immunology, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Centre, Xi’an, Shaanxi, China; Key Laboratory of Environment and Genes Related to Diseases (Xi’an Jiaotong University), Ministry of Education of China, Xi’an, Shaanxi, China
Woodvine Otieno Odhiambo: Department of Pathogenic Biology and Immunology, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Centre, Xi’an, Shaanxi, China; Key Laboratory of Environment and Genes Related to Diseases (Xi’an Jiaotong University), Ministry of Education of China, Xi’an, Shaanxi, China
Mingzhe Zheng: Department of Pathogenic Biology and Immunology, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Centre, Xi’an, Shaanxi, China; Key Laboratory of Environment and Genes Related to Diseases (Xi’an Jiaotong University), Ministry of Education of China, Xi’an, Shaanxi, China
Hua Zhang: Department of Pathogenic Biology and Immunology, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Centre, Xi’an, Shaanxi, China; Key Laboratory of Environment and Genes Related to Diseases (Xi’an Jiaotong University), Ministry of Education of China, Xi’an, Shaanxi, China
Yunfeng Ma: Department of Pathogenic Biology and Immunology, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Centre, Xi’an, Shaanxi, China; Key Laboratory of Environment and Genes Related to Diseases (Xi’an Jiaotong University), Ministry of Education of China, Xi’an, Shaanxi, China
Yanhong Ji: Department of Pathogenic Biology and Immunology, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Centre, Xi’an, Shaanxi, China; Key Laboratory of Environment and Genes Related to Diseases (Xi’an Jiaotong University), Ministry of Education of China, Xi’an, Shaanxi, China; Corresponding author at: School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Centre, No. 76 Yanta West Road, Xi’an, Shaanxi 710061, China.

Journal volume & issue: Vol. 22, no. 3
pp. 142 – 153

Abstract

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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

Published in Neoplasia: An International Journal for Oncology Research

ISSN: 1522-8002 (Print); 1476-5586 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Medicine: Internal medicine: Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Website: http://www.journals.elsevier.com/neoplasia/

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