Ca2+-Dependent Transcriptional Repressors KCNIP and Regulation of Prognosis Genes in Glioblastoma

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.

Transcriptome Analysis Reveals That Alfalfa Promotes Rumen Development Through Enhanced Metabolic Processes and Calcium Transduction in Hu Lambs

“…Although the differential expression of the ryanodine receptor was not observed in our alfalfa-supplemented lambs, the downregulation of the FAM20C gene, encoding Golgi serine/threonine protein kinase, can result in Ca 2+ release from sarcoplasmic reticulum (Pollak et al, 2017), which is consistent with these upregulated channel proteins and channel-binding proteins, suggesting that supplementary alfalfa increased [Ca 2+ ] i . The proteins encoded by the upregulated CAV3 gene and KCNIP2 gene can maintain calcium rhythms (Kamishima et al, 2007; Neant et al, 2018) to keep Ca 2+ transient. The increased [Ca 2+ ] i would be a signal for downstream muscle contraction (Ebashi and Endo, 1968), remodeling of muscle tissue (Trian et al, 2007), cell differentiation (Linta et al, 2013), and skin repair (Zhang and Cui, 2017).…”

The adaptive transition of glioblastoma stem cells and its implications on treatments

“… 33 Accumulation of p27 at G0 phase in qGSCs is associated with the maintenance of cells quiescence. 97 Factors like Ca2+ influx related genes expression (like CACNB1, CAPS, CACNA2D1, PKD2 and ORAI2), 98 the activity of Notch signaling pathway, 99 mitochondrial shape 96 and hypoxia and acidic niche 39 are also raised for their role in quiescence state.…”

Knockdown of STIM1 expression inhibits non-small-cell lung cancer cell proliferation in vitro and in nude mouse xenografts

“…With the identification of the molecular processes involved in pulmonary carcinogenesis, novel treatments targeting small molecules have emerged with encouraging results. For example, Ca 2+ signaling controls a wide variety of cell functions, such as secretion, gene transcription, cell proliferation and apoptosis [4][5][6]. Alterations of Ca 2+ signaling have emerged to an important factor in cancer progression [7,8].…”