Liu Wei, Zeng Yi, Hao Xinhui, Wang Xin, Liu Jiaxiang, Gao Tianyang, Wang Mengdi, Zhang Jingyao, Huo Miaomiao, Hu Ting, Ma Tianyu, Zhang Die, Teng Xu, Yu Hefen, Zhang Min, Yuan Baowen, Huang Wei, Yang Yunkai, Wang Yan
Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, P. R. 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, P. R. China.
Cancer Commun (Lond). 2023 Oct;43(10):1117-1142. doi: 10.1002/cac2.12479. Epub 2023 Sep 1.
Proteins containing the Jumonji C (JmjC) domain participated in tumorigenesis and cancer progression. However, the mechanisms underlying this effect are still poorly understood. Our objective was to investigate the role of Jumonji and the AT-rich interaction domain-containing 2 (JARID2) - a JmjC family protein - in breast cancer, as well as its latent association with obesity.
Immunohistochemistry, The Cancer Genome Atlas, Gene Expression Omnibus, and other databases were used to analyze the expression of JARID2 in breast cancer cells. Growth curve, 5-ethynyl-2-deoxyuridine (EdU), colony formation, and cell invasion experiments were used to detect whether JARID2 affected breast cancer cell proliferation and invasion. Spheroidization-based experiments and xenotumor transplantation in NOD/SCID mice were used to examine the association between JARID2 and breast cancer stemness. RNA-sequencing, Kyoto Encyclopedia of Genes and Genomes, and Gene Set Enrichment Analysis were used to identify the cell processes in which JARID2 participates. Immunoaffinity purification and silver staining mass spectrometry were conducted to search for proteins that might interact with JARID2. The results were further verified using co-immunoprecipitation and glutathione S-transferase (GST) pull-down experiments. Using chromatin immunoprecipitation (ChIP) sequencing, we sought the target genes that JARID2 and metastasis-associated protein 1 (MTA1) jointly regulated; the results were validated by ChIP-PCR, quantitative ChIP (qChIP) and ChIP-reChIP assays. A coculture experiment was used to explore the interactions between breast cancer cells and adipocytes.
In this study, we found that JARID2 was highly expressed in multiple types of cancer including breast cancer. JARID2 promoted glycolysis, lipid metabolism, proliferation, invasion, and stemness of breast cancer cells. Furthermore, JARID2 physically interacted with the nucleosome remodeling and deacetylase (NuRD) complex, transcriptionally repressing a series of tumor suppressor genes such as BRCA2 DNA repair associated (BRCA2), RB transcriptional corepressor 1 (RB1), and inositol polyphosphate-4-phosphatase type II B (INPP4B). Additionally, JARID2 expression was regulated by the obesity-associated adipokine leptin via Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) pathway in the breast cancer microenvironment. Analysis of various online databases also indicated that JARID2/MTA1 was associated with a poor prognosis of breast cancer.
Our data indicated that JARID2 promoted breast tumorigenesis and development, confirming JARID2 as a target for cancer treatment.
含有Jumonji C（JmjC）结构域的蛋白质参与肿瘤发生和癌症进展。然而，这种作用的潜在机制仍知之甚少。我们的目的是研究Jumonji和含AT丰富相互作用结构域2（JARID2）——一种JmjC家族蛋白——在乳腺癌中的作用，以及它与肥胖的潜在关联。
采用免疫组织化学、癌症基因组图谱、基因表达综合数据库等分析JARID2在乳腺癌细胞中的表达。通过生长曲线、5-乙炔基-2'-脱氧尿苷（EdU）、集落形成和细胞侵袭实验检测JARID2是否影响乳腺癌细胞的增殖和侵袭。基于球状体形成的实验和在NOD/SCID小鼠中的异种肿瘤移植用于研究JARID2与乳腺癌干性之间的关联。利用RNA测序、京都基因与基因组百科全书和基因集富集分析来确定JARID2参与的细胞过程。进行免疫亲和纯化和银染质谱分析以寻找可能与JARID2相互作用的蛋白质。结果通过共免疫沉淀和谷胱甘肽S-转移酶（GST）下拉实验进一步验证。使用染色质免疫沉淀（ChIP）测序，我们寻找JARID2和转移相关蛋白1（MTA1）共同调控的靶基因；结果通过ChIP-PCR、定量ChIP（qChIP）和ChIP-reChIP分析进行验证。采用共培养实验探索乳腺癌细胞与脂肪细胞之间的相互作用。
在本研究中，我们发现JARID2在包括乳腺癌在内的多种癌症中高表达。JARID2促进乳腺癌细胞的糖酵解、脂质代谢、增殖、侵袭和干性。此外，JARID2与核小体重塑和去乙酰化酶（NuRD）复合物发生物理相互作用，转录抑制一系列肿瘤抑制基因，如BRCA2 DNA修复相关蛋白（BRCA2）、RB转录共抑制因子1（RB1）和II B型肌醇多磷酸-4-磷酸酶（INPP4B）。此外，在乳腺癌微环境中，JARID2的表达受肥胖相关脂肪因子瘦素通过Janus激酶2/信号转导和转录激活因子3（JAK2/STAT3）途径的调控。对各种在线数据库的分析还表明，JARID2/MTA1与乳腺癌的不良预后相关。
我们的数据表明JARID2促进乳腺肿瘤发生和发展，证实JARID2可作为癌症治疗的靶点。
