Description:
Abstract Quiescence (G0) represents an assortment of reversible, cell cycle-arrested states that are resistant to unfavorable conditions and associated with cancer persistence. G0 involves regulated gene expression with selective mRNA expression and decreased canonical translation. Low mTOR activity in G0 activates the cap complex inhibitor, eIF4EBP, and impairs canonical translation. The alternative translation mechanisms in G0 remain to be uncovered. Our data show that microRNAs, regulatory, non-coding RNAs that target distinct mRNAs to alter gene expression, can associate with alternative complexes and translation factors to regulate specific mRNA translation in G0. One subset of transcripts expressed in G0 includes specific mRNAs recruited by an FXR1a-associated microRNP (microRNA-protein complex) for translation activation in G0 mammalian cells. MicroRNPs predominantly mediate repression and downregulation; however, FXR1a-microRNP lacks conventional microRNP repressors, and instead, contains a specific RNA binding protein isoform, FXR1a. FXR1a promotes translation and is overexpressed and associated with poor prognosis in several cancers. Our data reveal that microRNA-mediated activation requires target mRNAs with unadenylated/ shortened poly(A) tails to avoid the roles of PABP in enhancing microRNA-mediated downregulation and in canonical translation that is impaired in G0. Instead of canonical translation factors that are inhibited by eIF4EBP in G0, we find alternative translation factors—a non-canonical 5’cap binding factor and an eIF4G homolog that interacts with the ribosome—are recruited by the 3’-UTR binding FXR1a-microRNP, and promote specific mRNA translation. Our data show that G0 leukemic cells are chemoresistant and their translation profile is similar to surviving leukemic cells that are isolated after clinical therapy. We find expression of critical cytokines and immune regulators in G0. Significantly, inhibiting these immune regulators in resistant G0 cancer cells reduces their survival and chemoresistance. These data reveal a specialized translation mechanism in G0 cancer cells that promotes specific mRNA translation in these conditions of reduced canonical translation, and is important for chemoresistance. Citation Format: Syed I. Bukhari, Samuel S. Truesdell, Sooncheol Lee, Swapna Kollu, Anthony Classon, Myriam Boukhali, Esha Jain, Richard D. Mortensen, Akiko Yanagiya, Ruslan Sadreyev, Wilhelm Haas, Shobha Vasudevan. Specialized microRNP and translation mechanisms in quiescent cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4997. doi:10.1158/1538-7445.AM2017-4997