The lysine demethylase KDM2A, also known as JHDM1A, FBXL11 or Ndy2, demethylates histone H3 at lysine K36 ( 3). In the nucleosome, DNA is packaged by two sets of core histones, H2A, H2B, H3 and H4, whose amino acid residues can be regulated by diverse post-translational modifications such as methylation, acetylation or phosphorylation ( 2). The pathogenic role of histone modification leads to various cancers ( 1). The data provides a new potential mechanism and strategy for MM treatment. These results reveal a novel function of KDM2A through ubiquitin ligase activity by targeting PFKFB3 to induce proliferation, glycolysis and angiogenesis in MM cells. Clinically, MM patients with low KDM2A and high PFKFB3 levels have shown worse prognosis. Several angiogenic cytokines are also downregulated in MM. We further reveal that KDM2A targets PFKFB3 for ubiquitination and degradation to inhibit angiogenesis. Previous study showed that KDM2A and PFKFB3 promoted angiogenesis in various tumor cells. Specifically, we defined that one of the key enzymes of glycolysis PFKFB3 (6-phosphofructo-2-kinase) is ubiquitylated by KDM2A which suppresses MM cell proliferation. In the present study, we aimed to characterize the functional significance of KDM2A in multiple myeloma (MM) disease progression. However, many biological processes are mediated by KDM2A independently by its histone demethylation activity. The lysine demethylase KDM2A (also known as JHDM1A or FBXL11) demethylates histone H3 at lysine K36 which lead to epigenetic regulation of cell proliferation and tumorigenesis. 5Department of Hematology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.4Department of Hematology, The First Affiliated Hospital, Weifang Medical University, Weifang, China.3Department of Dermatology, Weifang Hospital of Traditional Chinese Medicine, Weifang, China.2Department of Oncology, Clinical Research Center, Affiliated Hospital of Weifang Medical University, Weifang, China.1Department of Hematology, Laboratory for Stem Cell and Regenerative Medicine, Clinical Research Center, Affiliated Hospital of Weifang Medical University, Weifang, China.Xinling Liu 1†, Jiaqiu Li 2†, Zhanju Wang 1, Jie Meng 1, Aihong Wang 1, Xiaofei Zhao 3, Qilu Xu 4, Zhen Cai 5* and Zhenbo Hu 1*