含有Jumonji C（JmjC）结构域的蛋白参与了肿瘤发生和癌症进展。然而，这种影响的机制仍然不清楚。我们的目标是研究Jumonji和AT富集互作结构域2（JARID2） - 一种JmjC家族蛋白在乳腺癌中的作用，以及其与肥胖的潜在关联。 我们使用免疫组化、The Cancer Genome Atlas、Gene Expression Omnibus和其他数据库来分析JARID2在乳腺癌细胞中的表达。生长曲线、5-乙炔基-2-脱氧尿嘧啶（EdU）、群体形成和细胞侵袭实验被用于检测JARID2是否影响乳腺癌细胞的增殖和侵袭。基于球体化的实验和NOD/SCID小鼠异种肿瘤移植用于检查JARID2与乳腺癌干细胞性的关联。RNA测序、Kyoto Encyclopedia of Genes and Genomes和Gene Set Enrichment Analysis被用于确定JARID2参与的细胞过程。免疫亲和纯化和银染质谱技术被用来寻找可能与JARID2相互作用的蛋白。结果进一步使用共免疫沉淀和谷胱甘肽S-转移酶（GST）下拉实验进行验证。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；结果经ChIP-PCR、定量ChIP（qChIP）和ChIP-重新immunoprecipitation（ChIP-reChIP）验证。在胎脂联培养实验中，研究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促进了乳腺癌细胞的糖酵解、脂质代谢、增殖、侵袭和干细胞性。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，通过转录抑制一系列肿瘤抑制基因，如乳腺癌相关蛋白2（BRCA2）、RB转录共抑制因子1（RB1）和肌醇多磷酸-4-磷酸酶II B（INPP4B）。此外，JARID2的表达受肥胖相关脂肪因子瘦素通过Janus激酶2/信号转导子及转录激活子3（JAK2/STAT3）途径在乳腺癌微环境中调控。对各种在线数据库的分析还表明JARID2/MTA1与乳腺癌预后不良有关。 我们的数据表明JARID2促进了乳腺肿瘤的发生和发展，证实JARID2是癌症治疗的一个靶点。©2023The Authors。由澳大利亚约翰·威立出版的Cancer Communications代表中山大学肿瘤中心发表。

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.© 2023 The Authors. Cancer Communications published by John Wiley & Sons Australia, Ltd. on behalf of Sun Yat-sen University Cancer Center.