Abstract
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 one of the possible therapeutic challenges to significantly improve anti-cancer treatment regimens for GBM. Ca2+ signaling is an important regulator of tumorigenesis in GBM, and the transition from proliferation to quiescence involves the modification of the kinetics of Ca2+ influx through store-operated channels due to an increased capacity of the mitochondria of quiescent GSLC to capture Ca2+. Therefore, the identification of new therapeutic targets requires the analysis of the calcium-regulated elements at transcriptional levels. In this review, we focus onto the direct regulation of gene expression by KCNIP proteins (KCNIP1–4). These proteins constitute the class E of Ca2+ sensor family with four EF-hand Ca2+-binding motifs and control gene transcription directly by binding, via a Ca2+-dependent mechanism, to specific DNA sites on target genes, called downstream regulatory element (DRE). The presence of putative DRE sites on genes associated with unfavorable outcome for GBM patients suggests that KCNIP proteins may contribute to the alteration of the expression of these prognosis genes. Indeed, in GBM, KCNIP2 expression appears to be significantly linked to the overall survival of patients. In this review, we summarize the current knowledge regarding the quiescent GSLCs with respect to Ca2+ signaling and discuss how Ca2+ via KCNIP proteins may affect prognosis genes expression in GBM. This original mechanism may constitute the basis of the development of new therapeutic strategies.
Highlights
Among tumors of the central nervous system, glioblastomas (GBMs) are the most aggressive and lethal primary astrocytic tumors in adults, with very poor prognosis (Louis et al, 2016; Lapointe et al, 2018)
According to the cancer stem cell model, recurrence in glioblastoma multiform (GBM) is attributed to a small sub-population of tumor cells called glioblastoma stem-like cells (GSLCs)
On GSLCs lines, established from surgical resections of primary GBMs, we showed that change in Ca2+ homeostasis is an important actor of the transition from proliferation to quiescence
Summary
Among tumors of the central nervous system, glioblastomas (GBMs) are the most aggressive and lethal primary astrocytic tumors in adults, with very poor prognosis (Louis et al, 2016; Lapointe et al, 2018). Ca2+ is an important regulator of gene expression This occurs either indirectly, via changes in the transactivating properties of transcription factors following the activation of Ca2+-dependent kinases and/or phosphatases (Dolmetsch, 2001; West et al, 2001; Kornhauser et al, 2002; Spotts et al, 2002), or directly via EF hand Ca2+-binding proteins which belongs to a group of four proteins (KCNIP1–4) (Mellström et al, 2008). KCNIP proteins are known to control gene transcription directly by binding, via a Ca2+-dependent mechanism, to specific DNA sites, called DRE, of target genes. Its transcripts are timely and spatially present in the presumptive neural territories In this in vivo model, loss of function experiments indicate that Kcnip is a Ca2+-dependent transcriptional repressor that controls the size of the neural plate by regulating the proliferation of neural progenitors (Néant et al, 2015)
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