Differential expression of a novel voltage gated potassium channel – Kv 1.5 in astrocytomas and its impact on prognosis in glioblastoma

Arvind, Sharma; Arivazhagan, Arimappamagan; Santosh, .; Chandramouli, Balasubramanian

doi:10.3109/02688697.2011.583365

Cited by 26 publications

(18 citation statements)

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“…(32)). In contrast, expression of KCNQ1 and of Kv1.5 has been reported to be inversely correlated with clinical aggression in gastrointestinal tumors (33) and in lymphoma and gliomas (34-36), respectively. Thus, deregulated expression of potassium ion channels is common in cancer but the mechanisms underlying their deregulation remain largely ill-defined.…”

Section: Resultsmentioning

confidence: 99%

“…Whether a relative reduction in DNA methylation at these gene promoters contributes to channel over-expression remains to be elucidated. With respect to the six loci with increased methylation in Ewing sarcoma, only down regulation of KCNA5 (Kv1.5) has been implicated in cancer pathogenesis (34-37), thus leading us to continue to focus our studies on this channel. Significantly, KCNA5 promoter methylation was detected in both Ewing sarcoma tumors and cell lines confirming that, in at least some Ewing sarcoma cells, polycomb-dependent repression of the locus is complemented by CpG-island DNA methylation (Figure 2B).…”

Section: Resultsmentioning

confidence: 99%

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Promoter Methylation Analysis Reveals That KCNA5 Ion Channel Silencing Supports Ewing Sarcoma Cell Proliferation

Ryland

Hawkins

Weisenberger

et al. 2016

Molecular Cancer Research

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Polycomb proteins are essential regulators of gene expression in stem cells and development. They function to reversibly repress gene transcription via post-translational modification of histones and chromatin compaction. In many human cancers, genes that are repressed by polycomb in stem cells are subject to more stable silencing via DNA methylation of promoter CpG islands. Ewing sarcoma is an aggressive bone and soft tissue tumor that is characterized by over-expression of polycomb proteins. This study investigates the DNA methylation status of polycomb target gene promoters in Ewing sarcoma tumors and cell lines and observes that the promoters of differentiation genes are frequent targets of CpG-island DNA methylation. In addition, the promoters of ion channel genes are highly differentially methylated in Ewing sarcoma compared to non-malignant adult tissues. Ion channels regulate a variety of biological processes, including proliferation, and dysfunction of these channels contributes to tumor pathogenesis. In particular, reduced expression of the voltage-gated Kv1.5 channel has been implicated in tumor progression. These data show that DNA methylation of the KCNA5 promoter contributes to stable epigenetic silencing of Kv1.5 channel. This epigenetic repression is reversed by exposure to the DNA methylation inhibitor decitabine, which inhibits Ewing sarcoma cell proliferation through mechanisms that include restoration of Kv1.5 channel function. Implications This study demonstrates that promoters of ion channels are aberrantly methylated in Ewing sarcoma and that epigenetic silencing of KCNA5 contributes to tumor cell proliferation, thus providing further evidence of the importance of ion channel dyregulation to tumorigenesis.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Promoter Methylation Analysis Reveals That KCNA5 Ion Channel Silencing Supports Ewing Sarcoma Cell Proliferation

Ryland

Hawkins

Weisenberger

et al. 2016

Molecular Cancer Research

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“…Kv1.5 is thus an attractive target for the treatment of atrial arrhythmias [13,[23][24][25][26][27][28][29][30][31][32]. Kv1.5 is further expressed in several tumor cells and participates in the regulation of adhesion, proliferation and sensitivity to apoptosis [33][34][35][36][37][38][39]. Thus, Kv1.5 has been considered a potential target against tumor growth [40].…”

Section: Introductionmentioning

confidence: 99%

Downregulation of Kv1.5 K⁺Channels by the AMP-Activated Protein Kinase

Mia¹,

Muñoz²,

Pakladok³

et al. 2012

Cell Physiol Biochem

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Background: The voltage gated K⁺ channel Kv1.5 participates in the repolarization of a wide variety of cell types. Kv1.5 is downregulated during hypoxia, which is known to stimulate the energy-sensing AMP-activated serine/threonine protein kinase (AMPK). AMPK is a powerful regulator of nutrient transport and metabolism. Moreover, AMPK is known to downregulate several ion channels, an effect at least in part due to stimulation of the ubiquitin ligase Nedd4- 2. The present study explored whether AMPK regulates Kv1.5. Methods: cRNA encoding Kv1.5 was injected into Xenopus oocytes with and without additional injection of wild-type AMPK (α1 β 1γ1), of constitutively active ^γR70QAMPK (α1 β 1γ1(R70Q)), of inactive mutant ^αK45RAMPK (α1(K45R)β1γ1), or of Nedd4-2. Kv1.5 activity was determined by two-electrode voltage-clamp. Moreover, Kv1.5 protein abundance in the cell membrane was determined by chemiluminescence and immunostaining with subsequent confocal microscopy. Results: Coexpression of wild-type AMPK^WT and constitutively active AMPK^γR70Q, but not of inactive AMPK^αK45R significantly reduced Kv1.5-mediated currents. Coexpression of constitutively active AMPKγR70Q further reduced Kv1.5 K⁺ channel protein abundance in the cell membrane. Co-expression of Nedd4-2 similarly downregulated Kv1.5-mediated currents. Conclusion: AMPK is a potent regulator of Kv1.5. AMPK inhibits Kv1.5 presumably in part by activation of Nedd4- 2 with subsequent clearance of channel protein from the cell membrane.

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“…Therefore, tyrosine phosphorylation of hK v 1.5 channels could also be important in maintaining normal cellular function of these types of cells. Moreover, K v 1.5 channels are also expressed in several tumour cells and participate in the modulation of cell adhesion, proliferation and apoptosis (Bonnet et al, 2007;Ousingsawat et al, 2007;Arvind et al, 2012). Thus, K v 1.5 channels has been considered to be a potential target to regulate tumour growth (Felipe et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

Genistein and tyrphostin AG556 decrease ultra‐rapidly activating delayed rectifier K⁺ current of human atria by inhibiting EGF receptor tyrosine kinase

Xiao

Zhang

et al. 2017

British J Pharmacology

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BACKGROUND AND PURPOSEThe ultra-rapidly activating delayed rectifier K + current I Kur (encoded by K v 1.5 or KCNA5) plays an important role in human atrial repolarization. The present study investigates the regulation of this current by protein tyrosine kinases (PTKs). EXPERIMENTAL APPROACHWhole-cell patch voltage clamp technique and immunoprecipitation and Western blotting analysis were used to investigate whether the PTK inhibitors genistein, tyrphostin AG556 (AG556) and PP2 regulate human atrial I Kur and hKv1.5 channels stably expressed in HEK 293 cells. KEY RESULTSHuman atrial I Kur was decreased by genistein (a broad-spectrum PTK inhibitor) and AG556 (a highly selective EGFR TK inhibitor) in a concentration-dependent manner. Inhibition of I Kur induced by 30 μM genistein or 10 μM AG556 was significantly reversed by 1 mM orthovanadate (a protein tyrosine phosphatase inhibitor). Similar results were observed in HEK 293 cells stably expressing hK v 1.5 channels. On the other hand, the Src family kinase inhibitor PP2 (1 μM) slightly enhanced I Kur and hK v 1.5 current, and the current increase was also reversed by orthovanadate. Immunoprecipitation and Western blotting analysis showed that genistein, AG556, and PP2 decreased tyrosine phosphorylation of hK v 1.5 channels and that the decrease was countered by orthovanadate. CONCLUSION AND IMPLICATIONSThe PTK inhibitors genistein and AG556 decrease human atrial I Kur and cloned hK v 1.5 channels by inhibiting EGFR TK, whereas the Src kinase inhibitor PP2 increases I Kur and hK v 1.5 current. These results imply that EGFR TK and the soluble Src kinases may have opposite effects on human atrial I Kur .Abbreviations EGFR, EGF receptor; I Kur , ultra-rapidly activating delayed rectifier potassium current; PP2, 3-(4-chlorophenyl) 1-(1,1-dimethylethyl)-1H-pyrazolo [3,4-d] pyrimidin-4-amine; PTK, protein tyrosine kinase; TK, protein kinase; tyrphostin AG556, AG556

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Differential expression of a novel voltage gated potassium channel – Kv 1.5 in astrocytomas and its impact on prognosis in glioblastoma

Abstract: Kv1.5 expression occurs more in DA, when compared to high grade astrocytoma. GBM patients with higher Kv1.5 expression had better survival, though not reaching statistical significance.

Cited by 26 publications

References 26 publications

Promoter Methylation Analysis Reveals That KCNA5 Ion Channel Silencing Supports Ewing Sarcoma Cell Proliferation

Promoter Methylation Analysis Reveals That KCNA5 Ion Channel Silencing Supports Ewing Sarcoma Cell Proliferation

Downregulation of Kv1.5 K⁺Channels by the AMP-Activated Protein Kinase

Genistein and tyrphostin AG556 decrease ultra‐rapidly activating delayed rectifier K⁺ current of human atria by inhibiting EGF receptor tyrosine kinase

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Differential expression of a novel voltage gated potassium channel – Kv 1.5 in astrocytomas and its impact on prognosis in glioblastoma

Abstract: Kv1.5 expression occurs more in DA, when compared to high grade astrocytoma. GBM patients with higher Kv1.5 expression had better survival, though not reaching statistical significance.

Cited by 26 publications

References 26 publications

Promoter Methylation Analysis Reveals That KCNA5 Ion Channel Silencing Supports Ewing Sarcoma Cell Proliferation

Promoter Methylation Analysis Reveals That KCNA5 Ion Channel Silencing Supports Ewing Sarcoma Cell Proliferation

Downregulation of Kv1.5 K+Channels by the AMP-Activated Protein Kinase

Genistein and tyrphostin AG556 decrease ultra‐rapidly activating delayed rectifier K+ current of human atria by inhibiting EGF receptor tyrosine kinase

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Product

Resources

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Downregulation of Kv1.5 K⁺Channels by the AMP-Activated Protein Kinase

Genistein and tyrphostin AG556 decrease ultra‐rapidly activating delayed rectifier K⁺ current of human atria by inhibiting EGF receptor tyrosine kinase