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Ca 2+ -Dependent Transcriptional Repressors KCNIP and Regulation Ca 2+ -Dependent Transcriptional Repressors KCNIP and Regulation of Prognosis Genes in Glioblastoma Isabelle Néant, Jacques Haiech, Marie-Claude Kilhoffer, Francisco Aulestia, Marc Moreau, Catherine Leclerc To cite this version: Isabelle Néant, Jacques Haiech, Marie-Claude Kilhoffer, Francisco Aulestia, Marc Moreau, et al.. Ca 2+ -Dependent Transcriptional Repressors KCNIP and Regulation of Prognosis Genes in Glioblas- toma. Frontiers in Molecular Neuroscience, Frontiers Media, 2018, 10.3389/fnmol.2018.00472. hal- 02329159 HAL Id: hal-02329159 https://hal.archives-ouvertes.fr/hal-02329159 Submitted on 23 Oct 2019 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. fnmol-11-00472 December 16, 2018 Time: 13:6 # 1 REVIEW published: 18 December 2018 doi: 10.3389/fnmol.2018.00472 Ca2C-Dependent Transcriptional Repressors KCNIP and Regulation of Prognosis Genes in Glioblastoma Isabelle Néant1, Jacques Haiech2, Marie-Claude Kilhoffer2, Francisco J. Aulestia3, Marc Moreau1 and Catherine Leclerc1* 1 Centre de Biologie du Développement (CBD), Centre de Biologie Intégrative (CBI), CNRS, UPS, Université de Toulouse, Toulouse, France, 2 Laboratoire d’Excellence Medalis, CNRS, LIT UMR 7200, Université de Strasbourg, Strasbourg, France, 3 Department of Basic Science and Craniofacial Biology, NYU College of Dentistry, New York, NY, United States Glioblastomas (GBMs) are the most aggressive and lethal primary astrocytic tumors in adults, with very poor prognosis. Recurrence in GBM is attributed to glioblastoma stem-like cells (GSLCs). The behavior of the tumor, including proliferation, progression, invasion, and significant resistance to therapies, is a consequence of the self-renewing properties of the GSLCs, and their high resistance to chemotherapies have been attributed to their capacity to enter quiescence. Thus, targeting GSLCs may constitute Edited by: one of the possible therapeutic challenges to significantly improve anti-cancer treatment Jose R. Naranjo, 2C Spanish National Research Council regimens for GBM. Ca signaling is an important regulator of tumorigenesis in (CSIC), Spain GBM, and the transition from proliferation to quiescence involves the modification Reviewed by: of the kinetics of Ca2C influx through store-operated channels due to an increased Ana Cristina Calvo, capacity of the mitochondria of quiescent GSLC to capture Ca2C. Therefore, the Universidad de Zaragoza, Spain Marisa Brini, identification of new therapeutic targets requires the analysis of the calcium-regulated Università degli Studi di Padova, Italy elements at transcriptional levels. In this review, we focus onto the direct regulation of Mario Vallejo, Instituto de Investigaciones gene expression by KCNIP proteins (KCNIP1–4). These proteins constitute the class Biomédicas Alberto Sols (IIBM), Spain E of Ca2C sensor family with four EF-hand Ca2C-binding motifs and control gene *Correspondence: transcription directly by binding, via a Ca2C-dependent mechanism, to specific DNA Catherine Leclerc sites on target genes, called downstream regulatory element (DRE). The presence of [email protected] putative DRE sites on genes associated with unfavorable outcome for GBM patients Received: 03 October 2018 suggests that KCNIP proteins may contribute to the alteration of the expression of Accepted: 04 December 2018 Published: 18 December 2018 these prognosis genes. Indeed, in GBM, KCNIP2 expression appears to be significantly Citation: linked to the overall survival of patients. In this review, we summarize the current 2C Néant I, Haiech J, Kilhoffer M-C, knowledge regarding the quiescent GSLCs with respect to Ca signaling and discuss Aulestia FJ, Moreau M and Leclerc C how Ca2C via KCNIP proteins may affect prognosis genes expression in GBM. This (2018) Ca2C-Dependent Transcriptional Repressors KCNIP original mechanism may constitute the basis of the development of new therapeutic and Regulation of Prognosis Genes strategies. in Glioblastoma. Front. Mol. Neurosci. 11:472. Keywords: Ca2C signaling, neuronal Ca2C sensors, KCNIP, glioblastoma multiform, cancer stem cells (CSC), doi: 10.3389/fnmol.2018.00472 quiescence Frontiers in Molecular Neuroscience| www.frontiersin.org 1 December 2018| Volume 11| Article 472 fnmol-11-00472 December 16, 2018 Time: 13:6 # 2 Néant et al. KCNIP Ca2C Sensors and Glioblastoma INTRODUCTION (SOCE) (Dong et al., 2017). These data exemplify the fact that Ca2C channels, pumps, and exchangers may represent potential Among tumors of the central nervous system, glioblastomas therapeutic targets. In this review, we will summarize the current (GBMs) are the most aggressive and lethal primary astrocytic knowledge regarding the quiescent GSLCs with respect to Ca2C tumors in adults, with very poor prognosis (Louis et al., signaling and describe an original mechanism by which Ca2C can 2016; Lapointe et al., 2018). More than 90% of the patients activate some genes involved in the prognosis of GBM in order show recurrence after therapies combining surgical resection, to propose new strategies to explore the molecular basis of GBM radiotherapy, and temozolomide (TMZ)-based chemotherapy, development for therapeutic issues. and the mean survival period rarely exceeds 2 years (Stupp et al., 2005). According to the cancer stem cell model, recurrence in GBM is attributed to a small sub-population of tumor cells called TRANSITION FROM PROLIFERATION TO glioblastoma stem-like cells (GSLCs). These GSLCs have stem- QUIESCENCE AND Ca2C SIGNALING like properties and are responsible for the initiation and the growth of the tumors (Visvader and Lindeman, 2008). Indeed, Quiescent cells are non-proliferative cells, arrested in a specific the GSLCs provide all the subtypes of cells that comprise the phase of the cell cycle called G0 (Coller et al., 2006). Quiescence tumor including some pseudo-endothelial cells (Ricci-Vitiani is not a prolonged G1 phase and in contrary to the cell- et al., 2010). GSLCs are characterized by a molecular signature cycle arrest observed in differentiation or senescence, it is which combines markers of neural and/or embryonic stem reversible. Transcriptional profiling data reveal that quiescent cells and of mesenchymal cells. Numerous studies support the stem cells are characterized by a common set of genes which proposal that the behavior of the tumor, including proliferation, are either downregulated, these are genes associated with progression, invasion, and significant resistance to therapies, cell-cycle progression (i.e., CCNA2, CCNB1, and CCNE2), or is determined by the self-renewing properties of the GSLCs upregulated and classified as tumor suppressors, including the (Stupp et al., 2005; Bao et al., 2006; Hegi et al., 2006; Stupp cyclin-dependent kinase inhibitor p21 (CDKN1A) and the G0/G1 and Hegi, 2007; Murat et al., 2008). More importantly, this high switch gene 2 (G0S2)(Yamada et al., 2012; Cheung and Rando, resistance capacity to TMZ treatment have been attributed to 2013). Quiescence represents a strategy for GSLCs to evade slow cycling or relatively quiescent GSLCs (Pistollato et al., 2010; killing. It is thus vital to better characterize the quiescent Deleyrolle et al., 2011). Quiescent GSLCs have been identified GSLCs and to understand the mechanisms involved in the in vivo in a mouse model of GBM (Chen et al., 2012) and transition from a proliferative to a quiescence state. Quiescence in human GBM tumors (Ishii et al., 2016). Thus, targeting is actively regulated by signals provided by the stem cell GSLCs and their stem cell-like properties may constitute one microenvironment. In GBM, quiescent cells are found close to of the possible therapeutic challenges to significantly improve necrotic tissues, in specific niches characterized by a hypoxic anti-cancer treatment regimens for GBM. (Pistollato et al., 2010; Persano et al., 2011; Ishii et al., 2016) and Ca2C is a crucial second messenger (Carafoli and Krebs, acidic microenvironment (Garcia-Martin et al., 2006; Honasoge 2016) that controls a wide variety of cell functions from cell et al., 2014). proliferation and apoptosis to organogenesis (Berridge et al., A recent study suggests that Ca2C is an important regulator 2000; Machaca, 2011; Moreau et al., 2016). Thus, the intracellular of the balance between quiescence and proliferation in Ca2C concentration ([Ca2C]i) is tightly regulated and involves hematopoietic stem cell (HSC) (Umemoto et al., 2018). In Ca2C channels, pumps, and exchangers both at the plasma HSCs, re-entry into cell-cycle requires Ca2C influx through membrane and at the membrane of endoplasmic reticulum, Cav1 voltage-dependent Ca2C channel and the resultant mitochondria, or Golgi apparatus (Bootman, 2012; Humeau activation of mitochondria. Recent findings in our group et al., 2018). In addition, changes in [Ca2C]i do not proceed showed that Ca2C signaling is also required for GBM stem cells in a stereotypical manner. The Ca2C signal can be described quiescence. On GSLCs lines, established from surgical resections by its amplitude (variations of [Ca2C]i levels) and by its
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