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Therapeutic Potential of the Mirna–ATM Axis in the Management of Tumor Radioresistance Abdol-Hossein Rezaeian1, Hashem Khanbabaei2, and George A

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Therapeutic Potential of the Mirna–ATM Axis in the Management of Tumor Radioresistance Abdol-Hossein Rezaeian1, Hashem Khanbabaei2, and George A Published OnlineFirst November 25, 2019; DOI: 10.1158/0008-5472.CAN-19-1807 CANCER RESEARCH | REVIEW Therapeutic Potential of the miRNA–ATM Axis in the Management of Tumor Radioresistance Abdol-Hossein Rezaeian1, Hashem Khanbabaei2, and George A. Calin3 ABSTRACT ◥ The ataxia-telangiectasia mutated (ATM) protein kinase is directly targeting the 30-untranslated region of ATM mRNA. widely known for its function as a chief mobilizer of the DNA This review addresses the therapeutic application and molecular damage response (DDR) upon DNA double-strand breaks. mechanisms that underlie the intricate interactions between ATM orchestrates the DDR by modulating the expression of miRNAs and ATM. It also describes therapeutic delivery of various miRNAs through several mechanisms. On the other miRNAs in different environments such as hypoxic tumor hand, a set of miRNAs contribute to tight regulation of ATM by microenvironments. Introduction Besides phosphorylating a wide range of downstream proteins, ATM controls DDR via regulation of miRNAs, which are small RNAs Eukaryotic cells have evolved a highly organized cascade of events that do not codify for proteins but regulate protein expression in called DNA damage response (DDR) to counteract the potentially physiologic conditions or diseases (5, 6). Accumulating evidence has deleterious effects of DNA damage caused by intrinsic and extrinsic revealed that ATM controls miRNA expression through multiple genotoxic stresses. DNA double-strand breaks (DSB) are among the steps, including transcription, processing, nucleocytoplasmic export, most severe genomic lesions that occur during radiotherapy. In and activation in response to DNA damage. On the other hand, several response to DSBs, the ataxia-telangiectasia mutated (ATM) protein, 0 small regulatory miRNAs have been identified that could bind to the 3 which is one of the earliest and main kinases, triggers a major signaling 0 untranslated region (3 UTR) of ATM and repress its expression. These pathway to arrest cell-cycle progression and activate DNA repair to data indicate cross-talk between miRNA and the ATM signaling prevent genomic instability or induce apoptosis when the damage is pathway, which could be a potential axis to be considered in combi- beyond repair (1). Meanwhile, it was reported that hypoxia-induced nation therapy for cancer (7). Therapeutic manipulation of dysregu- activity of ATM is independent of the presence of DNA breaks (2). lated miRNAs in vitro and in vivo has become more plausible owing to Oxidation of ATM directly induces ATM activation and, in turn, advances in chemically modified oligonucleotides and delivery sys- hyperphosphorylation of the histone H2AX in the absence of DNA tems. Therefore, in this review, we discuss the cross-talk between DSBs and the MRE11–RAD50–NBS1 (MRN) complex (3). Of note, we miRNAs and ATM signaling and potential therapeutic applications of discovered that hyperphosphorylation of H2AX by ATM stabilizes the ATM–miRNA axis in patients with cancer. hypoxia-inducible factor 1a (HIF1a) and promotes HIF1a–driven tumorigenesis in hypoxic tumor microenvironment (4). We hypoth- ATM regulates transcription of miRNAs esize that radiotherapy not only breaks DNA to arrest the cell cycle and DNA damage–induced activation of ATM phosphorylates several induces apoptosis for cancer treatment but also promotes oncogenic transcription factors that participate in regulation of miRNA expres- pathways, in part, via ATM activation in hypoxic tumor microenvi- sion (Fig. 1A). These miRNAs might be involved in the DDR through ronment independent of DNA damage signaling. Therefore, ionizing targeting key components of the DDR pathways. In response to IR, radiation (IR) may activate ATM, which drives tumorigenesis in ATM phosphorylates zinc finger E-box binding homeobox 1 (ZEB1), hypoxic tumor microenvironment, which must be critically consid- which stabilizes CHK1 and represses transcription of miR-205-5p, a ered in cancer treatment. miRNA that impairs DNA repair by targeting ZEB1 and the ubiquitin- conjugating enzyme (Ubc13; refs. 8, 9). Thus, activated ATM enhances DNA repair and radioresistance, partly through downregulation of 1Department of Molecular and Cellular Oncology, The University of Texas MD miR-205. Furthermore, ATM phosphorylates cAMP-responsive ele- 2 Anderson Cancer Center, Houston, Texas. Department of Medical Physics, ment-binding protein 1 (CREB), which results in reduced binding of Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, this protein to the promoter region of miR-335, a miRNA that directly Iran. 3Departments of Experimental Therapeutics and Leukemia and the Center for RNA Interference and Non-Coding RNA, The University of Texas MD binds to CtIP, a protein with a critical role in DNA end resection and Anderson Cancer Center, Houston, Texas. recruitment of BRCA1 to DSBs (10, 11). Overexpression of miR-335 Note: Supplementary data for this article are available at Cancer Research results in reduced CtIP levels, post-IR colony survival, and BRCA1 foci Online (http://cancerres.aacrjournals.org/). formation in HeLa cells. Therefore, miR-335 is a promising candidate radiosensitizer for further preclinical and clinical evaluation (11). A.-H. Rezaeian and H. Khanbabaei contributed equally to this article. Upon DNA damage, ATM also mediates p53 activation via several Corresponding Authors: George A. Calin, The University of Texas MD Anderson mechanisms, such as CHK2-mediated phosphorylation of p53 (12). In Cancer Center, So Campus Research Bldg 3 (3SCR4.3424), 1881 East Road, Unit turn, p53 binds directly to the promoter regions of specific miRNAs 1950, Houston, TX 77054. Phone: 713-792-5461; Fax: 713-745-4528; E-mail: [email protected]; and Abdol-Hossein Rezaeian, [email protected] and regulates their expression, including miR-34 family, miR-192/ miR-215, miR-145, miR-15/16, miR-107, and miR-200 family (13–16). Cancer Res 2020;80:139–50 P53-regulated miRNAs contribute to tumor suppression through doi: 10.1158/0008-5472.CAN-19-1807 induction of cell-cycle arrest, apoptosis, and senescence as well as Ó2019 American Association for Cancer Research. metastasis impairment. Interestingly, in p53-deficient cells, ATM AACRJournals.org | 139 Downloaded from cancerres.aacrjournals.org on September 23, 2021. © 2020 American Association for Cancer Research. Published OnlineFirst November 25, 2019; DOI: 10.1158/0008-5472.CAN-19-1807 Rezaeian et al. A B P Resistant to cytotoxic agents P Sensitive to cytotoxic agents ATM ATM P PPPP P P53 DDX1 KSRP BRCA1 AKT P38 P H2AX Drosha Drosha Drosha Drosha P P P P P MK2 Exportin 5 miR-21 let-7 miR-205 miR-335 miR-630 miR-34 miR-34a Nup153 P PPP P P P Nucleus HIF1α Snail1 ZEB1 CREB ΔNP63α p53 Cytoplasm Figure 1. ATM regulates miRNA transcription and maturation. A, Following DNA damage, activated ATM phosphorylates several transcription factors, which in turn regulate transcription of miRNAs. Phosphorylation of these transcription factors, which is dependent on the cell context, tumor stage, and tumor microenvironment, may increase or decrease sensitivity of tumors to treatment with cytotoxic agents. B, ATM-dependent maturation of a set of miRNAs is regulated in three steps. i, ATM phosphorylates several RNA-binding proteins (KSRP, DDX1, p53, and BRCA1), leading to enhanced interaction between them and pri-miRNAs and increased pri-miRNA processing activity by Drosha microprocessors. ii, ATM, via the AKT-Nup153 pathway, enhances the interaction between Nup153 and Exportin-5, increasing nuclear export of pre-miRNAs. iii, ATM-phosphorylated DNp63a binds to the promoter region of Dicer and induces its expression upon exposure to cisplatin. mediates miR-34c induction via an alternative pathway that involves the 30UTRs of target mRNAs, tumor cell–derived exosomal miR-21 p38 MAPK signaling, resulting in repression of c-Myc, a proto- could bind to and activate human Toll-like receptor 8 (TLR8) in oncogene known to cause DNA damage (17). In addition, Snail1, an macrophages, resulting in NF-kB pathway activation and secretion of epithelial-to-mesenchymal transition (EMT) transcription factor, the proinflammatory and prometastatic cytokines IL6 and TNFa, was identified to be phosphorylated by ATM, leading to promotion consequently promoting tumorigenesis and metastasis (31). Further- of tumor invasion and metastasis (18). Activated Snail1 may exert its more, HIF1a directly represses miR-34a expression in p53-deficient oncogenic effects partly via suppression of let-7 expression (19). colorectal cancer cells under hypoxic condition (23). Repression of Moreover, following DNA damage, ATM activates GATA4, which miR-34a is necessary for hypoxia-induced EMT, chemoresistance, and in turn transcribes miR-146a, a miRNA that is overexpressed in metastasis. Interestingly, p53 induces miR-107 expression, which in DNA damage–induced senescence and downregulates TRAF6, which turn directly targets and represses HIF1a expression under hypoxia. was identified to be critical to recruitment of ATM via monoubiqui- P53-induced miR-107 inhibits tumor growth and angiogenesis (32). tination of H2AX for activation of HIF1a signaling under hypoxic Taken together, these findings demonstrate that ATM regulates condition (20). transcription of several tumor-suppressive miRNAs upon DNA dam- In addition, hypoxia-induced activation of ATM regulates miRNA age. Meanwhile, ATM induces transcription of some oncomiRs upon transcription. Instantly, ATM activates HIF1a through different
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