Conditional Deletion of Eaf1 Induces Murine Prostatic Intraepithelial Neoplasia in Mice

• Published in: Neoplasia (New York, N.Y.) N.Y.), 2019-08, Vol.21 (8), p.752-764
• Main Authors: Pascal, Laura E., Su, Fei, Wang, Dan, Ai, Junkui, Song, Qiong, Wang, Yujuan, O'Malley, Katherine J., Cross, Brian, Rigatti, Lora H., Green, Anthony, Dhir, Rajiv, Wang, Zhou
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; Cell Line, Tumor; Disease Models, Animal; Gene Deletion; Gene Expression Regulation, Neoplastic; Gene Targeting; Genetic Loci; Genetic Predisposition to Disease; Humans; Immunohistochemistry; Male; Mice; Mice, Knockout; Neoplasm Grading; Original article; Prostatic Intraepithelial Neoplasia - genetics; Prostatic Intraepithelial Neoplasia - metabolism; Prostatic Intraepithelial Neoplasia - pathology; Prostatic Neoplasms - genetics; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Transcription Factors - chemistry; Transcription Factors - genetics
• ISSN: 1476-5586; 1522-8002; 1476-5586
• DOI: 10.1016/j.neo.2019.05.005

ELL-associated factor 1 is a transcription elongation factor that shares significant homology and functional similarity to the androgen-responsive prostate tumor suppressor ELL-associated factor 2. EAF2 is frequently down-regulated in advanced prostate cancer and Eaf2 deletion in the mouse induced the development of murine prostatic intraepithelial neoplasia. Here we show that similar to EAF2, EAF1 is frequently down-regulated in advanced prostate cancer. Co-downregulation of EAF1 and EAF2 occurred in 40% of clinical specimens with Gleason score >7. We developed and characterized a murine model of prostate-epithelial specific deletion of Eaf1 in the prostate and crossed it with our previously generated mouse with conventional deletion of Eaf2. The prostates of Eaf1 deletion mice displayed murine prostatic intraepithelial neoplasia lesions with increased proliferation and inflammation. Combined deletion of Eaf1 and Eaf2 in the murine model induced an increased incidence in mPIN lesions characterized by increased proliferation and CD3+ T cells and CD19+ B cells infiltration compared to individual deletion of either Eaf1 or Eaf2 in the murine prostate. These results suggest that EAF1 may play a tumor suppressive role in the prostate. Cooperation between EAF1 and EAF2 may be important for prostate maintaining prostate epithelial homeostasis, and concurrent loss of these two tumor suppressors may promote prostate tumorigenesis and progression.