SFEBES2021 Oral Communications Endocrine Cancer and Late Effects (6 abstracts)
A novel MiR-346-Directed DNA damage mechanism is regulated by its interaction with long non-coding RNA, NORAD, in prostate cancer
Claire Fletcher 1 , Folake Orafidiya 1 , Lin Deng 1 , Wei Yuan 2 , Marc Lorentzen 1 , Oliwia Cyran 1 , Anabel Varela-Carver 1 , Theodora Constantin 1 , Felix Dobbs 3 , Ines Figueiredo 2 , Bora Gurel 2 , Eileen Parkes 4 , Denisa Bogdan 2 , Ronnie Pereira 5 , Shuang (George) Zhao 6 , Antje Neeb 2 , Fadi Issa 4 , Joanna Hester 4 , Hiromi Kudo 1 , Yang Liu 7 , Yiannis Philippou 4 , Robert Bristow 5 , Karen Knudsen 8,9 , Richard Bryant 4 , Felix Feng 10 , Simon Reed 3 , Ian Mills 4 , Johann de Bono 2 & Charlotte Bevan 1
1Imperial College London, London, United Kingdom; 2Institute of Cancer Research, London, United Kingdom; 3Cardiff University, Cardiff, United Kingdom; 4University of Oxford, Oxford, United Kingdom; 5University of Manchester, Manchester, United Kingdom; 6University of Wisconsin-Madison, Madison, USA; 7Veracyte, Inc., San Diego, USA; 8Thomas Jefferson University, Philadelphia, USA; 9American Cancer Society and American Cancer Society Cancer Action Network, Atlanta, USA; 10University of California, San Francisco, San Francisco, USA
MiR-346 is an Androgen Receptor (AR)-activating miR that associates with DNA damage response (DDR)-linked transcripts in prostate cancer (PC). MiR-346 induces rapid and extensive DNA damage in PC cells through chromatin association, activation of transcription, R-loop formation and DNA replication stress, leading to checkpoint activation and cell cycle arrest. MiR-346 interacts with lncRNA, NORAD, in PC cells, which functions to maintain mitosis, DDR, and chromosomal integrity, and rescues miR-346-induced DNA damage. High NORAD expression/activity are strongly correlated with adverse disease outcome, and with increased DDR in primary, but not metastatic PC. In contrast, miR-346 is associated with improved PC survival. Further, NORAD activity is regulated by miR-346, which disrupts NORAD:PUM2 interaction, leading to PUM2 destabilisation and derepression of PUM1/2 DDR targets in PC cells. RNA-seq reveals widespread miR-346 and shNORAD dysregulation of DNA damage, DNA replication and cell cycle processes. High resolution, amplification-free genome-wide mapping of double strand DNA breaks (DSBs) (INDUCE-seq) reveals that miR-346-induced DSBs occur preferentially at binding sites of the most highly-active transcription factors in PC cells, including c-Myc, FOXA1, HOXB13, and importantly, AR, resulting in target transcript downregulation. Contrastingly, NORAD drives target-directed miR decay (TDMD) of miR-346 as a novel genome protection mechanism: NORAD silencing increases mature miR-346 levels by several thousand-fold, and WT but not TDMD-mutant NORAD significantly rescues miR-346-induced DNA damage. Thus balance between NORAD and miR-346 activities determines DDR in PC. This first demonstration of DNA damage induced by a miR is of direct therapeutic relevance: miR-346 sensitizes PC cells to chemotherapy/PARP inhibition and induces in vivo tumour regression. It may be particularly effective as a therapeutic in the context of decreased NORAD observed in advanced PC, and in transcriptionally-hyperactive cancer cells. Its induction of DSBs at AR binding sites may synergise with androgen-deprivation therapy as a novel PC treatment strategy.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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