BRD4 regulates m6A of ESPL1 mRNA via interaction with ALKBH5 to modulate breast cancer progression.
10.1016/j.apsb.2024.12.037
- Author:
Haisheng ZHANG
1
;
Linlin LU
2
;
Cheng YI
1
;
Tao JIANG
1
;
Yunqing LU
1
;
Xianyuan YANG
1
;
Ke ZHONG
1
;
Jiawang ZHOU
1
;
Jiexin LI
1
;
Guoyou XIE
1
;
Zhuojia CHEN
3
;
Zongpei JIANG
4
;
Gholamreza ASADIKARAM
5
;
Yanxi PENG
6
;
Dan ZHOU
7
;
Hongsheng WANG
1
Author Information
1. Guangdong Provincial Key Laboratory of Chiral Molecule and Drug Discovery; State Key Laboratory of Anti-Infective Drug Discovery and Development; School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
2. Institute of Medical Sciences, the Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250033, China.
3. Sun Yat-sen University Cancer Center State Key Laboratory of Oncology in South China Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China.
4. Department of Nephrology, the Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510655, China.
5. Endocrinology and Metabolism Research Center, Institute of Basic and Clinical Physiology Sciences, Kerman University of Medical Sciences, Medical University Campus, Kerman 7616914115, Iran.
6. School of Public Health, Xiangnan University, Chenzhou 423000, China.
7. Department of Breast Surgery, the First People's Hospital of Foshan, Foshan 528100, China.
- Publication Type:Journal Article
- Keywords:
ALKBH5;
BRD4;
Breast cancer;
Cell cycle;
ESPL1;
RALY;
TRIM21;
m6A
- From:
Acta Pharmaceutica Sinica B
2025;15(3):1552-1570
- CountryChina
- Language:English
-
Abstract:
The interaction between m6A-methylated RNA and chromatin modification remains largely unknown. We found that targeted inhibition of bromodomain-containing protein 4 (BRD4) by siRNA or its inhibitor (JQ1) significantly decreases mRNA m6A levels and suppresses the malignancy of breast cancer (BC) cells via increased expression of demethylase AlkB homolog 5 (ALKBH5). Mechanistically, inhibition of BRD4 increases the mRNA stability of ALKBH5 via enhanced binding between its 3' untranslated regions (3'UTRs) with RNA-binding protein RALY. Further, BRD4 serves as a scaffold for ubiquitin enzymes tripartite motif containing-21 (TRIM21) and ALKBH5, resulting in the ubiquitination and degradation of ALKBH5 protein. JQ1-increased ALKBH5 then demethylates mRNA of extra spindle pole bodies like 1 (ESPL1) and reduces binding between ESPL1 mRNA and m6A reader insulin like growth factor 2 mRNA binding protein 3 (IGF2BP3), leading to decay of ESPL1 mRNA. Animal and clinical studies confirm a critical role of BRD4/ALKBH5/ESPL1 pathway in BC progression. Further, our study sheds light on the crosstalks between histone modification and RNA methylation.
