title: SRC-2-mediated coactivation of anti-tumorigenic target genes suppresses MYC-induced liver cancer.
abstract: Hepatocellular carcinoma (HCC) is the fifth most common solid tumor in the world and the third leading cause of cancer-associated deaths. A Sleeping Beauty-mediated transposon mutagenesis screen previously identified mutations that cooperate with MYC to accelerate liver tumorigenesis. This revealed a tumor suppressor role for Steroid Receptor Coactivator 2/Nuclear Receptor Coactivator 2 (Src-2/Ncoa2) in liver cancer. In contrast, SRC-2 promotes survival and metastasis in prostate cancer cells, suggesting a tissue-specific and context-dependent role for SRC-2 in tumorigenesis. To determine if genetic loss of SRC-2 is sufficient to accelerate MYC-mediated liver tumorigenesis, we bred Src-2-/- mice with a MYC-induced liver tumor model and observed a significant increase in liver tumor burden. RNA sequencing of liver tumors and in vivo chromatin immunoprecipitation assays revealed a set of direct target genes that are bound by SRC-2 and exhibit downregulated expression in Src-2-/- liver tumors. We demonstrate that activation of SHP (Small Heterodimer Partner), DKK4 (Dickkopf-4), and CADM4 (Cell Adhesion Molecule 4) by SRC-2 suppresses tumorigenesis in vitro and in vivo. These studies suggest that SRC-2 may exhibit oncogenic or tumor suppressor activity depending on the target genes and nuclear receptors that are expressed in distinct tissues and illuminate the mechanisms of tumor suppression by SRC-2 in liver.
authors.affiliation: Department of Molecular Biology, UT Southwestern Medical Center, Dallas, TX, United States of America.
authors.forename: Shruthy
authors.identifier: 0000-0002-2985-8284
authors.initials: S
authors.lastname: Suresh
authors.affiliation: Department of Molecular Biology, UT Southwestern Medical Center, Dallas, TX, United States of America.
authors.forename: Deniz
authors.identifier: 0000-0003-2393-7528
authors.initials: D
authors.lastname: Durakoglugil
authors.affiliation: Department of Molecular Biology, UT Southwestern Medical Center, Dallas, TX, United States of America.|Department of Immunology, Nantong University School of Medicine, Nantong, China.
authors.forename: Xiaorong
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, United States of America.
authors.forename: Bokai
authors.identifier: 0000-0003-0827-5757
authors.initials: B
authors.lastname: Zhu
authors.affiliation: Department of Molecular Genetics, UT Southwestern Medical Center, Dallas, TX, United States of America.
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Comerford
authors.affiliation: Department of Clinical Sciences, UT Southwestern Medical Center, Dallas, TX, United States of America.|McDermott Center for Human Growth and Development, UT Southwestern Medical Center, Dallas, TX, United States of America.
authors.forename: Chao
authors.identifier: 0000-0002-1838-0502
authors.initials: C
authors.lastname: Xing
authors.affiliation: Department of Clinical Sciences, UT Southwestern Medical Center, Dallas, TX, United States of America.|Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX, United States of America.
authors.forename: Xian-Jin
authors.identifier: 0000-0002-5698-0330
authors.initials: XJ
authors.lastname: Xie
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, United States of America.|Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, United States of America.
authors.forename: Brian
authors.initials: B
authors.lastname: York
authors.affiliation: Department of Molecular Biology, UT Southwestern Medical Center, Dallas, TX, United States of America.|Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX, United States of America.
authors.forename: Kathryn A
authors.initials: KA
authors.lastname: O'Donnell
mesh_terms: D000483:Alleles; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry; D063646:Carcinogenesis; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism*; D015815:Cell Adhesion Molecules / Q000378:metabolism; D049109:Cell Proliferation; D002470:Cell Survival; D047369:Chromatin Immunoprecipitation; D004251:DNA Transposable Elements; D005260:Female; D017353:Gene Deletion; D056945:Hep G2 Cells; D006801:Humans; D007136:Immunoglobulins / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008819:Mice, Nude; D016296:Mutagenesis; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D051958:Nuclear Receptor Coactivator 2 / Q000235:genetics / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D017423:Sequence Analysis, RNA
chemical_list: D000970:Antineoplastic Agents; C498601:CADM4 protein, human; D015815:Cell Adhesion Molecules; C442333:DKK4 protein, human; D004251:DNA Transposable Elements; D007136:Immunoglobulins; D036341:Intercellular Signaling Peptides and Proteins; C498001:NCOA2 protein, human; D051958:Nuclear Receptor Coactivator 2; D016271:Proto-Oncogene Proteins c-myc; D018160:Receptors, Cytoplasmic and Nuclear; C099713:nuclear receptor subfamily 0, group B, member 2