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, 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 to 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 research. 2016 Jun 16 [Epub ahead of print]
Neeraj Agarwal, Garrett M Dancik, Andrew Goodspeed, James C Costello, Charles Owens, Jason E Duex, Dan Theodorescu
the Departments of Surgery (Urology) and Pharmacology, University of Colorado., Department of Mathematics and Computer Science, Eastern Connecticut State University., Department of Pharmacology, University of Colorado., University of Colorado Comprehensive Cancer Center, University of Colorado., Department of Surgery, University of Colorado., Departments of Surgery (Urology) and Pharmacology, University of Colorado., Departments of Surgery and Pathology, University of Colorado Comprehensive Cancer Center .