IFNg, a potent cytokine known to modulate tumor immunity and tumoricidal effects, is highly elevated in patients with prostate cancer after radiation. In this study, we demonstrate that IFNg can induce epithelial-to-mesenchymal transition (EMT) in prostate cancer cells via the JAK-STAT signaling pathway, leading to the transcription of IFN-stimulated genes (ISG) such as IFN-induced tetratricopeptide repeat 5 (IFIT5). We unveil a new function of IFIT5 complex in degrading precursor miRNAs (pre-miRNA) that includes pre-miR-363 from the miR-106a-363 cluster as well as pre-miR-101 and pre-miR-128, who share a similar 5 0 -end structure with pre-miR-363. These suppressive miRNAs exerted a similar function by targeting EMT transcription factors in prostate cancer cells. Depletion of IFIT5 decreased IFNg-induced cell invasiveness in vitro and lung metastasis in vivo. IFIT5 was highly elevated in high-grade prostate cancer and its expression inversely correlated with these suppressive miRNAs. Altogether, this study unveils a prometastatic role of the IFNg pathway via a new mechanism of action, which raises concerns about its clinical application.Significance: A unique IFIT5-XRN1 complex involved in the turnover of specific tumor suppressive microRNAs is the underlying mechanism of IFNg-induced epithelial-tomesenchymal transition in prostate cancer.See related commentary by Liu and Gao, p. 1032

Cancer stem cell (CSC), the primary source of cancer-initiating population, is involved in cancer recurrence and drug-resistant phenotypes. This study demonstrates that the loss of DAB2IP, a novel Ras-GTPase activating protein frequently found in many cancer types, is associated with CSC properties. Mechanistically, DAB2IP is able to suppress stem cell factor receptor (c-kit or CD117) gene expression by interacting with a newly identified silencer in the c-kit gene. Moreover, DAB2IP is able to inhibit c-kit-PI3K-Akt-mTOR signaling pathway that increases c-myc protein to activate ZEB1 gene expression leading to the elevated CSC phenotypes. An inverse correlation between CD117 or ZEB1 and DAB2IP is also found in clinical specimens. Similarly, Elevated expression of ZEB1 and CD117 are found in the prostate basal cell population of DAB2IP knockout mice. Our study reveals that DAB2IP has a critical role in modulating CSC properties via CD117-mediated ZEB1 signaling pathway.

Altered androgen-receptor (AR) expression and/or constitutively active AR are commonly associated with prostate cancer (PCa) progression. Targeting AR remains a focal point for designing new strategy of PCa therapy. Here, we have shown that DAB2IP, a novel tumor suppressor in PCa, can inhibit AR-mediated cell growth and gene activation in PCa cells via distinct mechanisms. DAB2IP inhibits the genomic pathway by preventing AR nuclear translocation or phosphorylation and suppresses the non-genomic pathway via its unique functional domain to inactivate c-Src. Also, DAB2IP is capable of suppressing AR activation in an androgen-independent manner. In addition, DAB2IP can inhibit several AR splice variants showing constitutive activity in PCa cells. In DAB2IP(-/-) mice, the prostate gland exhibits hyperplastic epithelia, in which AR becomes more active. Consistently, DAB2IP expression inversely correlates with AR activation status particularly in recurrent or metastatic PCa patients. Taken together, DAB2IP is a unique intrinsic AR modulator in normal cells, and likely can be further developed into a therapeutic agent for PCa.

Background: Prostate cancer (PCa) is the second leading cause of cancer mortality in US. The majority of PCa mortality is due to the recurrent of metastatic castration resistant PCa. The acquisition of epithelial-to-mesenchymal transition (EMT) signifies PCa metastasis. In particular, altered microRNAs (miRNAs) expression is closely associated with PCa progression from prostatic intraepithelial neoplasia to metastatic adenocarcinoma. miRNAs are small noncoding RNAs regulating approximately 60% protein-coding genes by post-transcriptional suppression or translational inhibition. miRNA gene expression at post-transcriptional level becomes more complicated when multiple miRNAs derived from the same cluster generate a polycistronic primary transcript, and each individual miRNA displays different expression profile and functional role. miRNA-363 (miR-363) belongs to the miR-106a-363 cluster containing miR-106a, miR-18b, miR-20b, miR-19b-2, miR-92a-2 and miR-363. Unlike the other five miRNAs which are closely resemble to the oncogenic miR-17-92 cluster in their seed sequence and function, miR-363 has been implicated to play a tumor suppressor role in several types of cancer, indicating a different regulatory mechanism of miR-363 from the miR-106a-363 cluster. Interferon-induced tetratricopeptide repeat 5 (IFIT5) is first characterized as a viral RNA binding protein and has been shown to directly bind to cellular tRNA, which partially shared a structural similarity with precursor miRNAs (pre-miRNAs). However, until now, there is no report indicating the RNA recognition role of IFIT5 in miRNA biogenesis machinery. Results: In the present study, miR-363 was clearly identified as a tumor suppressor miRNA by inhibiting EMT in PCa cells via targeting slug/SNAI2. More importantly, we have demonstrated, for the first time, that IFIT5 is able to recognize a unique structure at the 5′ end of precursor miR-363, which facilitates pre-miR-363 degradation by the recruitment of a 5′-3′exoribonuclease, XRN1. Meanwhile, we have also shown that the significant elevation of IFIT5 is detected in several PCa cells undergone EMT leading to highly metastatic potential. In addition, an inverse correlation between miR-363 and IFIT5 mRNA level was found in human PCa specimens. Conclusion: We unveil IFIT5 complex as a new post-transcriptional regulatory mechanism specific for miR-363 turnover at the precursor stage, which determines the stability and unique functional role of miR-363 distinct from other oncogenic miRNA members in the miR-106a-363 cluster. Overall, this study provides an insight of miRNA biogenesis machinery in cancer metastasis and new strategies of therapeutic intervention of PCa. Citation Format: U-Ging Lo, Rey-Chen Pong, Diane Yang, Jiancheng Zhou, Leah Gandee, Shu-Fen Tseng, Jer-Tsong Hsieh. Identification of a new mechanism of microRNA turnover from miR-106a-363 cluster leading to epithelial-to-mesenchymal transition in prostate cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2873. doi:10.1158/1538-7445.AM2015-2873