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RUNX2 招募 NuRD(MTA1)/CRL4B 复合物促进乳腺癌的进展和骨转移。

RUNX2 recruits the NuRD(MTA1)/CRL4B complex to promote breast cancer progression and bone metastasis.

机构信息

Beijing Key Laboratory of Cancer Invasion and Metastasis Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, Beijing, 100069, China.

Key Laboratory of Cancer and Microbiome, State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.

出版信息

Cell Death Differ. 2022 Nov;29(11):2203-2217. doi: 10.1038/s41418-022-01010-2. Epub 2022 May 9.

DOI:10.1038/s41418-022-01010-2
PMID:35534547
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9613664/
Abstract

Runt-related transcription factor 2 (RUNX2) is an osteogenesis-related transcription factor that has emerged as a prominent transcription repressing factor in carcinogenesis. However, the role of RUNX2 in breast cancer metastasis remains poorly understood. Here, we show that RUNX2 recruits the metastasis-associated 1 (MTA1)/NuRD and the Cullin 4B (CUL4B)-Ring E3 ligase (CRL4B) complex to form a transcriptional-repressive complex, which catalyzes the histone deacetylation and ubiquitylation. Genome-wide analysis of the RUNX2/NuRD(MTA1)/CRL4B complex targets identified a cohort of genes including peroxisome proliferator-activated receptor alpha (PPARα) and superoxide dismutase 2 (SOD2), which are critically involved in cell growth, epithelial-to-mesenchymal transition (EMT) and invasion. We demonstrate that the RUNX2/NuRD(MTA1)/CRL4B complex promotes the proliferation, invasion, tumorigenesis, bone metastasis, cancer stemness of breast cancer in vitro and in vivo. Strikingly, RUNX2 expression is upregulated in multiple human carcinomas, including breast cancer. Our study suggests that RUNX2 is a promising potential target for the future treatment strategies of breast cancer.

摘要

runt 相关转录因子 2（RUNX2）是一种与成骨相关的转录因子，它已成为致癌作用中突出的转录抑制因子。然而，RUNX2 在乳腺癌转移中的作用仍知之甚少。在这里，我们表明 RUNX2 募集转移相关蛋白 1（MTA1）/NuRD 和 Cullin 4B（CUL4B）-环 E3 连接酶（CRL4B）复合物形成转录抑制性复合物，该复合物催化组蛋白去乙酰化和泛素化。对 RUNX2/NuRD（MTA1）/CRL4B 复合物靶基因的全基因组分析确定了一组基因，包括过氧化物酶体增殖物激活受体α（PPARα）和超氧化物歧化酶 2（SOD2），它们在细胞生长、上皮间质转化（EMT）和侵袭中起关键作用。我们证明，RUNX2/NuRD（MTA1）/CRL4B 复合物促进了乳腺癌的体外和体内增殖、侵袭、致瘤性、骨转移和癌症干性。引人注目的是，RUNX2 的表达在多种人类癌中上调，包括乳腺癌。我们的研究表明，RUNX2 是未来乳腺癌治疗策略的一个有前途的潜在靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0733/9613664/2aad5bf97973/41418_2022_1010_Fig7_HTML.jpg
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