title: Steroid receptor coactivator-3 is a pivotal target of gambogic acid in B-cell Non-Hodgkin lymphoma and an inducer of histone H3 deacetylation.
abstract: Gambogic acid (GA), the active ingredient from gamboges, has been verified as a potent anti-tumor agent in many cancer cells. Nevertheless, its function in lymphoma, especially in B-cell Non-Hodgkin lymphoma (NHL), remains unclear. Amplification and/or overexpression of steroid receptor coactivator-3 (SRC-3) have been detected in multiple tumors and have confirmed its critical roles in carcinogenesis, progression, metastasis and therapy resistance in these cancers. However, no clinical data have revealed the overexpression of SRC-3 and its role in B-cell NHL. In this study, we demonstrated the anti-tumor effects of GA, which included cell growth inhibition, G1/S phase cell cycle arrest and apoptosis in B-cell NHL. We also verified that SRC-3 was overexpressed in B-cell NHL in both cell lines and lymph node samples from patients. The overexpressed SRC-3 was a central drug target of GA, and its down-regulation subsequently modulated down-stream gene expression, ultimately contributing to apoptosis. Silencing SRC-3 decreased the expression of Bcl-2, Bcl-6 and cyclin D3, but not of NF-κB and IκB-α. GA treatment did not inhibit the activation of AKT signaling pathway, but induced the deacetylation of histone H3 at lysine 9 and lysine 27. Down-regulated SRC-3 was observed to interact with more HDAC1 to mediate the deacetylation of H3. As the component of E3 ligase, Cullin3 was up-regulated and mediated the degradation of SRC-3. Our results demonstrate that GA is a potent anti-tumor agent that can be used for therapy against B-cell NHL, especially against those with an abundance of SRC-3.
authors.affiliation: Department of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
authors.forename: Zichu
authors.initials: Z
authors.lastname: Zhao
authors.affiliation: Department of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
authors.forename: Xia
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Wen
authors.affiliation: Department of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
authors.forename: Sha
authors.initials: S
authors.lastname: Yi
authors.affiliation: Department of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
authors.forename: Jingyu
authors.initials: J
authors.lastname: Hu
authors.affiliation: Department of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Ruan
authors.affiliation: Department of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Zhao
authors.affiliation: Department of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
authors.forename: Guohui
authors.initials: G
authors.lastname: Cui
authors.affiliation: Department of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China. Electronic address: junfangth@126.com.
authors.forename: Jun
authors.initials: J
authors.lastname: Fang
authors.affiliation: Department of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China. Electronic address: yanchen981@163.com.
authors.forename: Yan
authors.initials: Y
authors.lastname: Chen
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D020868:Gene Silencing; D056284:Histone Deacetylase 1 / Q000378:metabolism; D006657:Histones / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D016393:Lymphoma, B-Cell / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008239:Lysine / Q000378:metabolism; D051379:Mice; D058990:Molecular Targeted Therapy; D016328:NF-kappa B / Q000378:metabolism; D056921:Nuclear Receptor Coactivator 3 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015513:Oncogene Proteins / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D059807:S Phase Cell Cycle Checkpoints / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D044004:Xanthones / Q000494:pharmacology* / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D006657:Histones; D016328:NF-kappa B; D015513:Oncogene Proteins; D044004:Xanthones; C052659:gambogic acid; D056921:Nuclear Receptor Coactivator 3; D051057:Proto-Oncogene Proteins c-akt; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1; D008239:Lysine
keywords: Apoptosis; Deacetylation; Gambogic acid; Histone; Non-Hodgkin's lymphoma; SRC-3