t he Thoc1 r ibonucleoprotein and Prostate cancer Progression

Results THOC1 protein immunostaining increases with higher Gleason score and more advanced Tumor/Node/Metastasis stage. Time to biochemical recurrence is statistically significantly shorter for cancers with high THOC1 protein (log-rank P = .002, and it remains statistically significantly associated with biochemical recurrence after adjusting for Gleason score, clinical stage, and prostate-specific antigen levels (hazard ratio = 1.61, 95% confidence interval = 1.03 to 2.51, P = .04). Thoc1 deletion prevents prostate cancer progression in mice, but has little effect on normal tissue. Prostate cancer cells deprived of Thoc1 show gene expression defects that compromise cell growth. Conclusions Thoc1 is required to support the unique gene expression requirements of aggressive prostate cancer in mice. In humans, high THOC1 protein immunostaining associates with prostate cancer aggressiveness and recurrence. Thus, THOC1 protein is a functionally relevant molecular marker that may improve the identification of aggressive prostate cancers, potentially reducing overtreatment. JNCI J Natl Cancer Inst (20 14) 106(11): dju306

[1]  Andrea Califano,et al.  A Molecular Signature Predictive of Indolent Prostate Cancer , 2013, Science Translational Medicine.

[2]  C. Logothetis,et al.  Molecular classification of prostate cancer progression: foundation for marker-driven treatment of prostate cancer. , 2013, Cancer discovery.

[3]  Xiaoling Wang,et al.  The THO Ribonucleoprotein Complex Is Required for Stem Cell Homeostasis in the Adult Mouse Small Intestine , 2013, Molecular and Cellular Biology.

[4]  Charles Y. Lin,et al.  Transcriptional Amplification in Tumor Cells with Elevated c-Myc , 2012, Cell.

[5]  Carleen Cullinane,et al.  Inhibition of RNA polymerase I as a therapeutic strategy to promote cancer-specific activation of p53. , 2012, Cancer cell.

[6]  Benjamin J. Raphael,et al.  The Mutational Landscape of Lethal Castrate Resistant Prostate Cancer , 2012, Nature.

[7]  C. Koh,et al.  Overexpression of ribosomal RNA in prostate cancer is common but not linked to rDNA promoter hypomethylation , 2011, Oncogene.

[8]  Rosa Luna,et al.  Genome Instability and Transcription Elongation Impairment in Human Cells Depleted of THO/TREX , 2011, PLoS genetics.

[9]  Masaaki Komatsu,et al.  Autophagy: Renovation of Cells and Tissues , 2011, Cell.

[10]  G. Mazzini,et al.  Selective inhibition of rRNA transcription downregulates E2F-1: a new p53-independent mechanism linking cell growth to cell proliferation , 2011, Journal of Cell Science.

[11]  Katsuhiko Shirahige,et al.  Genome‐wide function of THO/TREX in active genes prevents R‐loop‐dependent replication obstacles , 2011, The EMBO journal.

[12]  R. Luna,et al.  Differential expression of THOC1 and ALY mRNP biogenesis/export factors in human cancers , 2011, BMC Cancer.

[13]  B. Foster,et al.  E2f binding-deficient Rb1 protein suppresses prostate tumor progression in vivo , 2010, Proceedings of the National Academy of Sciences.

[14]  C. Sander,et al.  Integrative genomic profiling of human prostate cancer. , 2010, Cancer cell.

[15]  Anthony D Whetton,et al.  THOC5/FMIP, an mRNA export TREX complex protein, is essential for hematopoietic primitive cell survival in vivo , 2010, BMC Biology.

[16]  Yanping Zhang,et al.  Signaling to p53: ribosomal proteins find their way. , 2009, Cancer cell.

[17]  Michael J. Emanuele,et al.  A Genome-wide RNAi Screen Identifies Multiple Synthetic Lethal Interactions with the Ras Oncogene , 2009, Cell.

[18]  Jianmin Wang,et al.  Thoc1 Deficiency Compromises Gene Expression Necessary for Normal Testis Development in the Mouse , 2009, Molecular and Cellular Biology.

[19]  Ji Luo,et al.  Principles of Cancer Therapy: Oncogene and Non-oncogene Addiction , 2009, Cell.

[20]  M. Loda,et al.  Differential Requirement of mTOR in Postmitotic Tissues and Tumorigenesis , 2009, Science Signaling.

[21]  T. Khoury,et al.  Relationships of hHpr1/p84/Thoc1 expression to clinicopathologic characteristics and prognosis in non-small cell lung cancer. , 2008, Annals of clinical and laboratory science.

[22]  G. Mazzini,et al.  Different effects of ribosome biogenesis inhibition on cell proliferation in retinoblastoma protein‐ and p53‐deficient and proficient human osteosarcoma cell lines , 2007, Cell proliferation.

[23]  Xiaoling Wang,et al.  Cancer cells and normal cells differ in their requirements for Thoc1. , 2007, Cancer research.

[24]  A. Flesken-Nikitin,et al.  Prostate cancer associated with p53 and Rb deficiency arises from the stem/progenitor cell-enriched proximal region of prostatic ducts. , 2007, Cancer research.

[25]  Xiaoling Wang,et al.  An allelic series for studying the mouse Thoc1 gene , 2007, Genesis.

[26]  John T. Wei,et al.  Integrative molecular concept modeling of prostate cancer progression , 2007, Nature Genetics.

[27]  David C. Corney,et al.  Synergy of p53 and Rb deficiency in a conditional mouse model for metastatic prostate cancer. , 2006, Cancer research.

[28]  W. Kaelin.  The Concept of Synthetic Lethality in the Context of Anticancer Therapy , 2005, Nature Reviews Cancer.

[29]  Xiaoling Wang,et al.  Human hHpr1/p84/Thoc1 Regulates Transcriptional Elongation and Physically Links RNA Polymerase II and RNA Processing Factors , 2005, Molecular and Cellular Biology.

[30]  R. Shiekhattar,et al.  Linking transcriptional elongation and messenger RNA export to metastatic breast cancers. , 2005, Cancer research.

[31]  Jonathan R Warner,et al.  What better measure than ribosome synthesis? , 2004, Genes & development.

[32]  A. Yamamoto,et al.  LC3, GABARAP and GATE16 localize to autophagosomal membrane depending on form-II formation , 2004, Journal of Cell Science.

[33]  Andrés Aguilera,et al.  Cotranscriptionally formed DNA:RNA hybrids mediate transcription elongation impairment and transcription-associated recombination. , 2003, Molecular cell.

[34]  M. Daly,et al.  PGC-1α-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes , 2003, Nature Genetics.

[35]  P. Pandolfi,et al.  Does the ribosome translate cancer? , 2003, Nature Reviews Cancer.

[36]  C. Compton,et al.  AJCC Cancer Staging Manual , 2002, Springer New York.

[37]  R. Schneiter,et al.  The Saccharomyces cerevisiae Hyperrecombination Mutanthpr1Δ Is Synthetically Lethal with Two Conditional Alleles of the Acetyl Coenzyme A Carboxylase Gene and Causes a Defect in Nuclear Export of Polyadenylated RNA , 1999, Molecular and Cellular Biology.

[38]  S. Elledge,et al.  The amino-terminal region of the retinoblastoma gene product binds a novel nuclear matrix protein that co-localizes to centers for RNA processing , 1994, The Journal of cell biology.