AbstractBackgroundProteins 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.MethodsImmunohistochemistry, 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.ResultsIn 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.ConclusionOur data indicated that JARID2 promoted breast tumorigenesis and development, confirming JARID2 as a target for cancer treatment.