Anti-tumor activity of CDYL2b in prostate cancer.

Prostate cancer is a leading cause of death among men, yet the molecular underpinnings of this malignancy are still not fully understood. We discovered that two histone demethylases driving prostate tumorigenesis, the JMJD2A and JMJD2B enzymes, suppressed transcription of the CDYL2 epigenetic reader gene. Bioinformatic analyses showed that low CDYL2 expression in prostate tumors was associated with more metastasis and disease recurrence as well as reduced survival. Out of the four predicted CDYL2 isoforms, all of which were capable of forming homo- and heteromers, only CDYL2b was appreciably expressed in prostate cancer cells and tightly associated with chromatin. Overexpression of CDYL2b in human DU145 and 22Rv1 prostate cancer cells decreased their growth and clonogenic activity in vitro as well as tumor expansion in nude mice, while CDYL2b downregulation stimulated LNCaP cell growth. RNA sequencing exposed that CDYL2b induced upregulation of transcription factor genes HES7, KLF17 and TBX6 and overexpression of those factors phenocopied to various degrees the anti-oncogenic effects of CDYL2b. Further JMJD2B, but not JMJD2A, robustly formed complexes with CDYL2b and antagonized CDYL2b in upregulating HES7 transcription. In conclusion, our data highlight that CDYL2b can suppress prostate tumorigenesis, while JMJD2A and JMJD2B may exert their pro-oncogenic functions in part through stifling CDYL2b transcription or CDYL2b activity. In addition, our study revealed that the developmental transcription factors TBX6 and HES7 may also suppress tumorigenesis.