Abstract 1825: Epithelial adherens junctions suppress the pro-tumorigenic MIR17HG lncRNA by recruiting RISC

Abstract The adherens junctions (AJs) are essential architectural elements of epithelial tissues. Compromised junctional integrity is a common precursor to colon cancer. Recently, we identified a novel mechanism whereby the AJs of non-transformed colon cells recruit the microprocessor and RISC, core elements of the RNAi machinery, as well as miRNAs, to suppress oncogenic mRNAs. Knockdown of the AJ component PLEKHA7, disrupts this RNAi-mediated signaling program, leading to pro-tumorigenic cell transformation. Interestingly, PLEKHA7 RNA-CLIP and subsequent RNA-Seq analysis identified association with numerous long non-coding RNAs (lncRNAs). While a number of lncRNAs have been associated with tumorigenesis, the underlying mechanisms of their regulation during tumor progression are still unclear. As lncRNAs can interact with the RNAi machinery, we hypothesize that the AJs regulate lncRNAs via this localized RNAi mechanism. Examination of PLEKHA7-depleted cells by RNA-seq revealed differential expression of 49 junction-associated lncRNAs. From this set, the top upregulated lncRNA is MIR17HG, an oncogenic polycistronic host transcript of the miR-17-92 cluster. Junctional localization of MIR17HG was confirmed by RNA-FISH. Adherens junctions destabilization by E-cadherin knockdown also led to the upregulation of MIR17HG, demonstrating the role of junctional integrity in MIR17HG suppression. Data from Ago2 knockdown, anti-miR, and miRNA mimic experiments show that PLEKHA7 suppresses the levels of the MIR17HG transcript through the junction-associated RISC and two miRNAs, miR-203a and miR-372. PLEKHA7 depletion also results in increased levels of a subset of MIR17HG hosted miRNAs, including miR-19a and miR-19b, both known cancer promoters. Ectopic expression of PLEKHA7 in the aggressive HCT116 colon cancer cells that lack endogenous PLEKHA7 expression, suppressed anchorage independent growth, as well as MIR17HG levels, which are elevated in these cells. We are currently examining the role of MIR17HG as a functional intermediate of PLEKHA7’s loss on colon cell transformation. In summary, our data point towards a novel mechanism of lncRNA regulation that tethers epithelial architecture with cell behavior. Note: This abstract was not presented at the meeting. Citation Format: Mary C. Bridges, Joyce Nair-Menon, Antonis Kourtidis. Epithelial adherens junctions suppress the pro-tumorigenic MIR17HG lncRNA by recruiting RISC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1825.