The PRMT6/PARP1/CRL4B Complex Regulates the Circadian Clock and Promotes Breast Tumorigenesis,Advanced Science

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The PRMT6/PARP1/CRL4B Complex Regulates the Circadian Clock and Promotes Breast Tumorigenesis
Advanced Science ( IF 14.3 ) Pub Date : 2023-03-20 , DOI: 10.1002/advs.202202737
Tianshu Yang _{1,

2} , Wei Huang ₂ , Tianyu Ma ₁ , Xin Yin ₂ , Jingyao Zhang ₁ , Miaomiao Huo ₁ , Ting Hu ₁ , Tianyang Gao ₃ , Wei Liu ₃ , Die Zhang ₁ , Hefen Yu ₂ , Xu Teng ₂ , Min Zhang ₁ , Hao Qin ₁ , Yunkai Yang ₁ , Baowen Yuan ₁ , Yan Wang _{1,

2}

Affiliation

Circadian rhythms, as physiological systems with self-regulatory functions in living organisms, are controlled by core clock genes and are involved in tumor development. The protein arginine methyltransferase 6 (PRMT6) serves as an oncogene in a myriad of solid tumors, including breast cancer. Hence, the primary aim of the current study is to investigate the molecular mechanisms by which the PRMT6 complex promotes breast cancer progression. The results show that PRMT6, poly(ADP-ribose) polymerase 1 (PARP1), and the cullin 4 B (CUL4B)-Ring E3 ligase (CRL4B) complex interact to form a transcription-repressive complex that co-occupies the core clock gene PER3 promoter. Moreover, genome-wide analysis of PRMT6/PARP1/CUL4B targets identifies a cohort of genes that is principally involved in circadian rhythms. This transcriptional-repression complex promotes the proliferation and metastasis of breast cancer by interfering with circadian rhythm oscillation. Meanwhile, the PARP1 inhibitor Olaparib enhances clock gene expression, thus, reducing breast carcinogenesis, indicating that PARP1 inhibitors have potential antitumor effects in high-PRMT6 expression breast cancer.

中文翻译：

PRMT6/PARP1/CRL4B 复合物调节昼夜节律时钟并促进乳腺肿瘤发生

昼夜节律作为生物体具有自我调节功能的生理系统，受核心生物钟基因控制，参与肿瘤的发生发展。蛋白质精氨酸甲基转移酶 6 (PRMT6) 在包括乳腺癌在内的多种实体瘤中充当癌基因。因此，当前研究的主要目的是研究PRMT6复合物促进乳腺癌进展的分子机制。结果表明，PRMT6、聚（ADP-核糖）聚合酶 1 (PARP1) 和 cullin 4 B (CUL4B)-Ring E3 连接酶 (CRL4B) 复合物相互作用，形成转录抑制复合物，共同占据核心时钟基因PER3启动子。此外，PRMT6/PARP1/CUL4B 靶标的全基因组分析确定了一组主要参与昼夜节律的基因。这种转录抑制复合物通过干扰昼夜节律振荡来促进乳腺癌的增殖和转移。同时，PARP1抑制剂Olaparib增强时钟基因表达，从而减少乳腺癌的发生，表明PARP1抑制剂在高PRMT6表达的乳腺癌中具有潜在的抗肿瘤作用。

更新日期：2023-03-20

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