Molecular Activation of the Kv11.1 Channel Reprograms EMT in Colon Cancer by Inhibiting TGFβ Signaling via Activation of Calcineurin

Eskandari, Najmeh; Senyuk, Vitalyi; Moore, Jennifer; Kalik, Zane M.; Luan, Qiyue; Papautsky, Ian; Moshiri, Arfa; Bocchetta, Maurizio; Salami, Seyed Alireza; Oryan, Shahrbanoo; Gentile, Sandro

doi:10.3390/cancers13236025

Cited by 9 publications

(6 citation statements)

References 43 publications

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“…Next, significant correlations were found between ZFHX4 and lots of ion channels. Eskandari et al reported that Kv11.1 channel reprogrammed EMT in colon cancer via regulating zinc finger homobox proteins [ 49 ], suggesting that ZFHX4 might also act as a mediator converting the signals from ion transporter activation to EMT occurrence and ECM reprogramming in ovarian cancer. Although ZFHX4 took an active part in promoting cancer metastasis, it functioned as a tumor suppressor in tumor proliferation.…”

Section: Discussionmentioning

confidence: 99%

A bioinformatics analysis: ZFHX4 is associated with metastasis and poor survival in ovarian cancer

Zong

et al. 2022

J Ovarian Res

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Background Metastasis was the major cause of the high mortality in ovarian cancer. Although some mechanisms of metastasis in ovarian cancer were proposed, few have been targeted in the clinical practice. In the study, we aimed to identify novel genes contributing to metastasis and poor clinical outcome in ovarian cancer from bioinformatics databases. Methods Studies collecting matched primary tumors and metastases from ovarian cancer patients were searched in the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were screened by software R language. Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis for the DEGs were implemented by Metascape. Venn diagram was plotted to present overlapping DEGs. The associations between the overlapping DEGs and prognosis were tested by Cox proportional hazard regression model using a cohort of ovarian cancer patients from the TCGA database. Genes affecting patients’ outcomes significantly were served as hub genes. The mechanisms of the hub genes in promoting ovarian cancer metastasis were then predicted by R software. Results Two gene expression profiles (GSE30587 and GSE73168) met the inclusion criteria and were finally analyzed. A total of 259 genes were significantly differentially expressed in GSE30587, whereas 712 genes were in GSE73168. In GSE30587, DEGs were mainly involved in extracellular matrix (ECM) organization; For GSE73168, most of DEGs showed ion trans-membrane transport activity. There were 9 overlapping genes between the two datasets (RUNX2, FABP4, CLDN20, SVEP1, FAM169A, PGM5, ZFHX4, DCN and TAS2R50). ZFHX4 was proved to be an independent adverse prognostic factor for ovarian cancer patients (HR = 1.44, 95%CI: 1.13–1.83, p = 0.003). Mechanistically, ZFHX4 was positively significantly correlated with epithelial-mesenchymal transition (EMT) markers (r = 0.54, p = 2.59 × 10−29) and ECM-related genes (r = 0.52, p = 2.86 × 10−27). Conclusions ZFHX4 might promote metastasis in ovarian cancer by regulating EMT and reprogramming ECM. For clinical applications, ZFHX4 was expected to be a prognostic biomarker for ovarian cancer metastasis.

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Section: Discussionmentioning

confidence: 99%

A bioinformatics analysis: ZFHX4 is associated with metastasis and poor survival in ovarian cancer

Zong

et al. 2022

J Ovarian Res

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“…Interestingly, 4-AP, an inhibitor of voltage-gated Kv1.1 and Kv1.2 channels, also blocks apoptotic extrusion 20 , suggesting a conserved activator for all cell extrusions (Fig 2D, Supplementary Fig 3A). Other channels are implicated in pleotropic diseases, like Kv11.1 in carcinomas 21,22 and heart arrhythmias 23 and the cystic fibrosis transmembrane receptor (CFTR) in cystic fibrosis 24 , suggesting possible new roles for misregulated extrusion in these diseases. While these findings were surprising and suggest interesting future studies, here, we focus solely on those that control the HES step.…”

Section: Mainmentioning

confidence: 99%

“…2D and A3A). Although most inhibitors were not toxic, the Clchannel SWELL1 is essential for cell survival 19 , requiring the addition of caspase inhibitor zVAD-fmk to its inhibitor DCPIB for all our Other channels are implicated in pleotropic diseases, like Kv11.1 in carcinomas 21,22 and heart arrhythmias 23 and the cystic fibrosis transmembrane receptor (CFTR) in cystic fibrosis 24 , suggesting possible new roles for misregulated extrusion in these diseases. While these findings were surprising and suggest interesting future studies, here, we focus solely on those that control the HES step.…”

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confidence: 99%

Voltage-dependent volume regulation controls epithelial cell extrusion and morphology

Mitchell

Pardo-Pastor

Zangle

et al. 2023

Preprint

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Epithelial cells work collectively to provide a protective barrier, yet also turn over rapidly by cell death and division. If the number of dying cells does not match those dividing, the barrier would vanish, or tumors can form. Mechanical forces and the stretch-activated ion channel (SAC) Piezo1 link both processes; stretch promotes cell division and crowding triggers cell death by initiating live cell extrusion1,2. However, it was not clear how particular cells within a crowded region are selected for extrusion. Here, we show that individual cells transiently shrink via water loss before they extrude. Artificially inducing cell shrinkage by increasing extracellular osmolarity is sufficient to induce cell extrusion. Pre-extrusion cell shrinkage requires the voltage-gated potassium channels Kv1.1 and Kv1.2 and the chloride channel SWELL1, upstream of Piezo1. Activation of these voltage-gated channels requires the mechano-sensitive Epithelial Sodium Channel, ENaC, acting as the earliest crowd-sensing step. Imaging with a voltage dye indicated that epithelial cells lose membrane potential as they become crowded and smaller, yet those selected for extrusion are markedly more depolarized than their neighbours. Loss of any of these channels in crowded conditions causes epithelial buckling, highlighting an important role for voltage and water regulation in controlling epithelial shape as well as extrusion. Thus, ENaC causes cells with similar membrane potentials to slowly shrink with compression but those with reduced membrane potentials to be eliminated by extrusion, suggesting a chief driver of cell death stems from insufficient energy to maintain cell membrane potential.

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“…Interestingly, it has been found that stimulation of the Kv11.1 channel with activator molecules produced an arrest in the G0/G1 phase of the cell-division cycle ( Lansu and Gentile, 2013 ). This event occurred in different cancer cells that are representative of breast ( Lansu and Gentile, 2013 ), skin ( Perez-Neut et al, 2016 ) and colon ( Eskandari et al, 2021 ) cancer indicating that Kv11.1 hyperactivity affects cancer cell proliferation independently of their histogenesis. Furthermore, a large variety of proliferation markers and signaling were severely altered in these cells.…”

Section: Applied Research Example 1—kv111 In Cancer Cell Proliferationmentioning

confidence: 99%

News and views on ion channels in cancer: is cancer a channelopathy?

Bell,

Leanza,

Gentile

et al. 2023

Front. Pharmacol.

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Ion channels are key signaling proteins found throughout the body; they are critical in many, wide-ranging physiological processes, from gene expression, sensory perception and processing to the cardiac action potential. When ion channel activity goes awry, for example, via mutation, damage or disrupted homeostasis, the outcome can result in causation, development and/or maintenance of disease. Ion channel dependent diseases have been dubbed channelopathies. Recent studies on the role of ion channels in cancer biology suggest that cancer is one such channelopathy. Many ion channels have now been implicated in the cellular processes that are affected in a multitude of cancers. In the last two decades, the field of ion channel and cancer research has been growing exponentially: a combination of developments in molecular biology, genetics, electrophysiology and automation have driven an explosion in our capabilities to interrogate ion channel pathways; how, why and where they go wrong and therapeutic interventions to correct their pathophysiology in cancer. A review of this vast and rapidly developing field would require a titanic tome to merely dimple the surface of research that has ballooned recently. In lieu of that huge undertaking—for the benefit of both authors and readers - this review discusses select examples of primary, applied and clinical research, aiming to shine a light on some of the more innovative and novel findings that this exciting field is excavating.

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Molecular Activation of the Kv11.1 Channel Reprograms EMT in Colon Cancer by Inhibiting TGFβ Signaling via Activation of Calcineurin

Cited by 9 publications

References 43 publications

A bioinformatics analysis: ZFHX4 is associated with metastasis and poor survival in ovarian cancer

A bioinformatics analysis: ZFHX4 is associated with metastasis and poor survival in ovarian cancer

Voltage-dependent volume regulation controls epithelial cell extrusion and morphology

News and views on ion channels in cancer: is cancer a channelopathy?

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