Abstract 4289: Involvement of the miR-6883 family and the circadian rhythm gene PER1 in the DNA damage response (DDR) and chemosensitivity

Abstract

Abstract PER1 is a circadian clock protein known to play a role in the cell cycle by directly regulating levels of Wee1 and indirectly influencing levels of Cdc2 and Cyclin B1. PER1 interaction with CHK2 promotes apoptosis in response to DNA damaging agents and loss of PER1 promotes chemoresistance. Expression of PER1 is found to be lost in most CRC tumors and restoring it sensitizes CRC cell lines to DNA damaging chemotherapeutic agents. However, the regulation of PER1 and its mechanism of repression in CRC remains unknown. We recently discovered and characterized miR-6883-5p, which is an intronic miRNA in the PER1 gene. Since PER1 is lost in most CRC it is suggested that the expression of miR-6883-5p is also lost. We showed that restoring the expression of miR-6883-5p via mimics induces G1-arrest and subsequent cell death in CRC cell lines. Similar to the overexpression of PER1, expression of miR-6883-5p with mimics increased the sensitivity of CRC cell lines to chemotherapeutic agents such as irinotecan and 5-FU. miR-6883-5p is a direct negative regulator of CDK4 and CDK6 and the downstream G1-S transition via RB. Our ongoing studies are characterizing molecular targets of miR-6883-5p and its role in the DNA damage response (DDR). FOXM1 is a downstream effector of CDK4 that plays a role in the DDR. Downregulation of FOXM1 sensitizes cells to DNA damage and restores chemosensitivity. We are further evaluating the direct effects of miR-6883-5p on FOXM1. FOXM1 is a member of the forkhead box (FOX) transcription factor family, expressed exclusively in proliferating cells. Its upregulation in different tumor types, including CRC promotes cell proliferation, EMT and chemoresistance. Interestingly, FOXM1 is also a repressor of the clock gene CRY2. Here, we hypothesize that miR-6883-5p mediated targeting of FOXM1 is crucial for the DDR, and, further, like CRY2, FOXM1 might have a role in regulating PER1 and thus miR-6883-5p endogenous levels. We report that miR-6883-5p levels are increased following exposure of tumor cells to chemotherapeutic agents that cause DNA damage. We are further elucidating the role of FOXM1 in the induction of miR-6883-5p under the DDR, and propose that induction of miR-6883-5p may provide a novel mechanism for tumor growth arrest in chemotherapy-exposed cells. Citation Format: Amriti R. Lulla, Avital Lev, Michael Slifker, David T. Dicker, Wafik S. El-Deiry. Involvement of the miR-6883 family and the circadian rhythm gene PER1 in the DNA damage response (DDR) and chemosensitivity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4289.