GON4L Drives Cancer Growth through a YY1-Androgen Receptor-CD24 Axis.
In principle, the inhibition of candidate gain-of-function genes defined through genomic analyses of large patient cohorts offers an attractive therapeutic strategy. In this study, we focused on changes in expression of CD24, a well-validated clinical biomarker of poor prognosis and a driver of tumor growth and metastasis, as a benchmark to assess functional relevance. Through this approach, we identified GON4L as a regulator of CD24 from screening a pooled shRNA library of 176 candidate gain-of-function genes. GON4L depletion reduced CD24 expression in human bladder cancer cells and blocked cell proliferation in vitro and tumor xenograft growth in vivo Mechanistically, GON4L interacted with transcription factor YY1, promoting its association with the androgen receptor to drive CD24 expression and cell growth. In clinical bladder cancer specimens, expression of GON4L, YY1, and CD24 was elevated compared with normal bladder urothelium. This pathway is biologically relevant in other cancer types as well, where CD24 and the androgen receptor are clinically prognostic, given that silencing of GON4L and YY1 suppressed CD24 expression and growth of human lung, prostate, and breast cancer cells. Overall, our results define GON4L as a novel driver of cancer growth, offering new biomarker and therapeutic opportunities. Cancer Res; 76(17); 5175-85. ©2016 AACR.
Department of Pharmacology, University of Colorado, Denver, Colorado. Department of Surgery (Urology), University of Colorado, Denver, Colorado.
Neeraj
N
Agarwal
Department of Mathematics and Computer Science, Eastern Connecticut State University, Willimantic, Connecticut.
Garrett M
GM
Dancik
Department of Pharmacology, University of Colorado, Denver, Colorado.
Andrew
A
Goodspeed
Department of Pharmacology, University of Colorado, Denver, Colorado. University of Colorado Comprehensive Cancer Center, Denver, Colorado.
James C
JC
Costello
Department of Pharmacology, University of Colorado, Denver, Colorado. Department of Surgery (Urology), University of Colorado, Denver, Colorado.
Charles
C
Owens
Department of Pharmacology, University of Colorado, Denver, Colorado. Department of Surgery (Urology), University of Colorado, Denver, Colorado.
Jason E
JE
Duex
Department of Pharmacology, University of Colorado, Denver, Colorado. Department of Surgery (Urology), University of Colorado, Denver, Colorado. University of Colorado Comprehensive Cancer Center, Denver, Colorado. dan.theodorescu@ucdenver.edu.
Dan
D
Theodorescu
D000818:Animals; D015153:Blotting, Western; D051927:CD24 Antigen / Q000378:metabolism*; D002295:Carcinoma, Transitional Cell / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000502:physiology; D056970:Co-Repressor Proteins; D004268:DNA-Binding Proteins; D005260:Female; D055785:Gene Knockdown Techniques; D064593:Heterografts; D006801:Humans; D047468:Immunoprecipitation; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction; D011944:Receptors, Androgen / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D001749:Urinary Bladder Neoplasms / Q000378:metabolism / Q000473:pathology*; D050986:YY1 Transcription Factor / Q000378:metabolism*
C410798:AR protein, human; D051927:CD24 Antigen; D056970:Co-Repressor Proteins; D004268:DNA-Binding Proteins; C514882:GON4L protein, human; D011944:Receptors, Androgen; D014157:Transcription Factors; D050986:YY1 Transcription Factor; C494698:YY1 protein, human