Abstract A01: ER stress disrupts circadian rhythms via miR-211

Abstract The Endoplasmic Reticulum, ER, senses both intracellular and extracellular stimuli that perturb the folding and maturation of secretory proteins that transit the ER. In the context of neoplastic growth, oncogenes such as c-Myc, H-Ras and BRAF trigger ER stress and activate the Unfolded Protein Response (UPR), a cell adaptive signaling pathway composed of three primary signal transducers, PERK, IRE-1 and ATF6. Bmal1 and Clock form a core heterodimeric transcription complex regulates both central and peripheral circadian rhythms. There are multiple lines of evidence suggesting that deregulation of circadian rhythms contribute to neoplastic cell growth, altered cellular metabolism and tumorigenesis. Analogously, UPR signaling contributes to tumor cell survival and tumor growth under conditions of micro-environmental and metabolic stress. However, whether UPR interactively regulates stress with the circadian clock is largely unknown. Herein, we describe the molecular mechanisms whereby UPR signaling integrates with the circadian clock. We provide evidence that ER stress-dependent activation of PERK alters circadian oscillations via micro-RNA 211-dependent suppression of BMAL1 and Clock. We provide evidence that the mechanism of regulation of BMAL1 versus clock is distinct, reflecting novel ability of miR-211 to function in both the nucleus and cytoplasm. We provide additional support for this model through using a mouse model to interrogate the role of PERK signaling in a liver specific response to ER stress. With regard to the impact of PERK signaling and circadian clock disruption in cancer, we assessed PERK-miR-211 signaling in c-Myc and MLL-AF9 driven malignancy. Here, expression of either c-Myc or MLL-AF9 expression was directly associated with activation of PERK-miR-211 and loss of both BMAL1 and Clock expression. We also found that Myc driven human Burkitt's lymphoma has PERK hyperactivation, higher miR-211 expression, and loss of circadian oscillations. As the Bmal1 promoter is hypermethylated in multiple lymphoma cancer cell lines, we hypothesize that this is likely to reflect the action of nuclear miR-211. Consistently, anti-miR211 partially released Bmal1 repression and Inhibition PERK or suppression miR-211 rescued circadian rhythms in lymphoma cells thereby affecting their survival and proliferation. Our data suggested a model where ER stress disrupts peripheral circadian rhythms via PERK-miR211-Bmal1/Clock pathway. Targeting activated ER stress or abnormal miR-211 expression to rescue circadian rhythms could be a new potential therapy for Myc- (perhaps also other oncogenes) driven hematological malignancy. Citation Format: Yiwen Bu, John Alan Diehl. ER stress disrupts circadian rhythms via miR-211. [abstract]. In: Proceedings of the AACR Special Conference on Noncoding RNAs and Cancer: Mechanisms to Medicines ; 2015 Dec 4-7; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2016;76(6 Suppl):Abstract nr A01.