Abstract The Abelson (c-Abl) proto-oncogene encodes a highly conserved nonreceptor protein tyrosine kinase that has been implicated in many cellular processes including regulation of cell growth and survival, oxidative stress and DNA-damage responses, actin dynamics and cell migration. Aberrant activity of this tyrosine kinase has been implicated in the stimulation of cancer growth and progression. Abl tyrosine kinase represents a target for specific anti-cancer therapy in prostate cancer and Abl inhibitors are being tested clinically for the treatment of prostate cancer bone metastasis. Here we report that Abl kinases are regulated by a novel microRNA- miR-4723-5p in prostate cancer. Expression profiling of miR-4723-5p expression in a cohort of prostate cancer clinical specimens showed that miR-4723-5p expression is widely attenuated in prostate cancer. Low miR-4723-5p expression was significantly correlated with poor survival outcome and tumor progression and recurrence in prostate cancer. Further, our analyses suggest that miR-4723-5p has significant potential as a disease biomarker for diagnosis and prognosis in prostate cancer. To evaluate the functional significance of decreased miR-4723-5p expression in prostate cancer, miR-4723-5p was reintroduced in prostate cancer cell lines followed by functional assays. The over expression of miR-4723-5p led to significant decreases in cell growth, clonability, invasion and migration. Importantly, miR-4723-5p reexpression led to dramatic induction of apoptosis in prostate cancer cell lines suggesting that miR-4723-5p is a pro-apoptotic microRNA that regulates prostate carcinogenesis. Analysis of putative miR-4723-5p targets showed that miR-4723-5p targets Integrin alpha 3 (ITGA3) and Methyl CpG binding protein (MeCP2) in addition to Abl1 and Abl2 kinases. In conclusion, we have identified a novel microRNA mediated regulation of Abl tyrosine kinases in prostate cancer. This study suggests that miR-4723-5p may be an attractive target for therapeutic intervention in prostate cancer. Citation Format: Sumit Arora, Sharanjot Saini, Shahana Majid, Varahram Shahryari, Soichiro Yamamura, Takeshi Chiyomaru, Shinichiro Fukuhara, Inik Chang, Guoren Deng, Yuichiro Tanaka, Rajvir Dahiya. MicroRNA 4723-5p is novel tumor suppressor microRNA in prostate cancer that directly regulates Abelson family of nonreceptor protein tyrosine kinases. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3068. doi:10.1158/1538-7445.AM2013-3068