Citations 2
Sleeping Beauty Insertional Mutagenesis Reveals Important Genetic Drivers of Central Nervous System Embryonal Tumors
Beckmann, Pauline J. , Larsson, Alex T. , Ostergaard, Jason, Wagner, Sandra, Rahrmann, Eric P. , Shamsan, Ghaidan A. , Otto, George M. , Williams, Rory L. , Wang, Jun , Lee, Catherine , Tschida, Barbara R. , Das, Paramita , Dubuc, Adrian M. , Moriarity, Branden S. , Picard, Daniel , Wu, Xiaochong , Rosemarie, Quincy , Krebs, Ryan D., Molan, Amy M. , Demer, Addison M. , Frees, Michelle M. , Rizzardi, Anthony E., Schmechel, Stephen C. , Jenkins, Robert B. , Wechsler‐Reya, Robert J. , Odde, David J. , Taylor, Michael D. , Sarver, Aaron L. , Largaespada, David A. , Rahrmann, Eric P , Shamsan, Ghaidan A , Williams, Rory L , Picard, Daniel , Rosemarie, Quincy , Odde, David J , Larson, Jon D. , Wagner, Sandra, Tschida, Barbara R , Rodríguez, Fausto J. , Krebs, Ryan D., Eberhart, Charles G. , Huang, Annie , Largaespada, David A.
Cancer Research | January 23, 2019 | Volume: 79 | Issue: 5 | Pages: 905-917
Abstract Medulloblastoma and central nervous system primitive neuroectodermal tumors (CNS-PNET) are aggressive, poorly differentiated brain tumors with limited effective therapies. Using Sleeping Beauty (SB) transposon mutagenesis, we identified novel genetic drivers of medulloblastoma and CNS-PNET. Cross-species gene expression analyses classified SB-driven tumors into distinct medulloblastoma and CNS-PNET subgroups, indicating they resemble human Sonic hedgehog and group 3 and 4 medulloblastoma and CNS neuroblastoma with FOXR2 activation. This represents the first genetically induced mouse model of CNS-PNET and a rare model of group 3 and 4 medulloblastoma. We identified several putative proto-oncogenes including Arhgap36, Megf10, and Foxr2. Genetic manipulation of these genes demonstrated a robust impact on tumorigenesis in vitro and in vivo. We also determined that FOXR2 interacts with N-MYC, increases C-MYC protein stability, and activates FAK/SRC signaling. Altogether, our study identified several promising therapeutic targets in medulloblastoma and CNS-PNET. Significance: A transposon-induced mouse model identifies several novel genetic drivers and potential therapeutic targets in medulloblastoma and CNS-PNET.
CBP Loss Cooperates with PTEN Haploinsufficiency to Drive Prostate Cancer: Implications for Epigenetic Therapy
Ding, Liya , Pan, Yunqian , Zhong, Jian , Regan, Kevin M., Wang, Liguo , Yu, Chunrong, Rizzardi, Anthony E., Zhang, Jun , Schmechel, Stephen C. , Cheville, John C. , Deursen, Jan van, Tindall, Donald J., Cheng, Liang , Chen, Daiwen , Liu, Ping , Cheng, Liang , Huang, Haojie , Wang, Liguo , Cheng, Liang
Cancer Research | February 3, 2014 | Volume: 74 | Issue: 7 | Pages: 2050-2061
Abstract Despite the high incidence and mortality of prostate cancer, the etiology of this disease is not fully understood. In this study, we develop functional evidence for CBP and PTEN interaction in prostate cancer based on findings of their correlate expression in the human disease. Cbppc−/−;Ptenpc+/− mice exhibited higher cell proliferation in the prostate and an early onset of high-grade prostatic intraepithelial neoplasia. Levels of EZH2 methyltransferase were increased along with its Thr350 phosphorylation in both mouse Cbp−/−; Pten+/− and human prostate cancer cells. CBP loss and PTEN deficiency cooperated to trigger a switch from K27-acetylated histone H3 to K27-trimethylated bulk histones in a manner associated with decreased expression of the growth inhibitory EZH2 target genes DAB2IP, p27KIP1, and p21CIP1. Conversely, treatment with the histone deacetylase inhibitor panobinostat reversed this switch, in a manner associated with tumor suppression in Cbppc−/−;Ptenpc+/− mice. Our findings show how CBP and PTEN interact to mediate tumor suppression in the prostate, establishing a central role for histone modification in the etiology of prostate cancer and providing a rationale for clinical evaluation of epigenetic-targeted therapy in patients with prostate cancer. Cancer Res; 74(7); 2050–61. ©2014 AACR.