GON4L Drives Cancer Growth through a YY1-Androgen Receptor-CD24 Axis
Neeraj Agarwal1, Garrett M Dancik2, Andrew Goodspeed3
1Department of Pharmacology, University of Colorado, Denver, Colorado. Department of Surgery (Urology), University of Colorado, Denver, Colorado.
Abstract:
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.
Insights
Researchers identified GON4L as a key driver of cancer growth by regulating CD24 expression. Inhibiting GON4L suppressed tumor growth in bladder, lung, prostate, and breast cancers, offering new therapeutic strategies.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- CD24 is a biomarker for poor prognosis and promotes tumor growth and metastasis.
- Gain-of-function genes identified in large patient cohorts present therapeutic targets.
Purpose of the Study:
- To identify regulators of CD24 expression and assess their role in cancer growth.
- To investigate the therapeutic potential of targeting identified regulators.
Main Methods:
- Screening of a pooled shRNA library against 176 candidate gain-of-function genes.
- Depletion of GON4L in human bladder cancer cells and assessment of proliferation and tumor xenograft growth.
- Analysis of GON4L, YY1, and CD24 expression in clinical cancer specimens and other cancer cell lines.
Main Results:
- GON4L was identified as a regulator of CD24 expression.
- GON4L depletion reduced CD24 levels, inhibited cell proliferation, and suppressed tumor xenograft growth.
- Elevated expression of GON4L, YY1, and CD24 was observed in bladder cancer tissues.
- Silencing GON4L and YY1 suppressed CD24 expression and growth in lung, prostate, and breast cancer cells.
Conclusions:
- GON4L is a novel driver of cancer growth, interacting with YY1 and the androgen receptor to promote CD24 expression.
- The GON4L-YY1-androgen receptor-CD24 pathway is crucial for cancer progression and offers potential therapeutic targets.
- GON4L represents a promising biomarker and therapeutic target across multiple cancer types.
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