Regulation of Ion Channel Function in Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes by Cancer Cell Secretion Through DNA Methylation

Rujia Zhong; Feng Zhang; Zhen Yang; Yingrui Li; Qiang Xu; Huan Lan; Siegfried Lang; Lukas Cyganek; Elke Burgermeister; Ibrahim El-Battrawy; Xiaobo Zhou; Ibrahim Akin; Martin Borggrefe

doi:10.3389/fcvm.2022.839104

Regulation of Ion Channel Function in Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes by Cancer Cell Secretion Through DNA Methylation

Front Cardiovasc Med. 2022 Feb 21:9:839104. doi: 10.3389/fcvm.2022.839104. eCollection 2022.

Authors

Rujia Zhong¹, Feng Zhang¹, Zhen Yang¹, Yingrui Li¹, Qiang Xu¹, Huan Lan², Siegfried Lang^{1

3}, Lukas Cyganek^{4

5}, Elke Burgermeister⁶, Ibrahim El-Battrawy^{1

3}, Xiaobo Zhou^{1

2

3}, Ibrahim Akin^{1

3}, Martin Borggrefe^{1

3}

Affiliations

¹ First Department of Medicine, Medical Faculty Mannheim, University Medical Centre Mannheim (UMM), University of Heidelberg, Mannheim, Germany.
² Key Laboratory of Medical Electrophysiology of Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, China.
³ DZHK (German Center for Cardiovascular Research), Partner Site, Mannheim, Germany.
⁴ Stem Cell Unit, Clinic for Cardiology and Pneumology, University Medical Center Göttingen, Göttingen, Germany.
⁵ DZHK (German Center for Cardiovascular Research), Partner Site, Göttingen, Germany.
⁶ Second Department of Medicine, Faculty of Medicine, University Medical Centre Mannheim (UMM), University of Heidelberg, Mannheim, Germany.

Abstract

Background: Cardiac dysfunction including arrhythmias appear frequently in patients with cancers, which are expected to be caused mainly by cardiotoxic effects of chemotherapy. Experimental studies investigating the effects of cancer cell secretion without chemotherapy on ion channel function in human cardiomyocytes are still lacking.

Methods: The human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) generated from three healthy donors were treated with gastrointestinal (GI) cancer (AGS and SW480 cells) medium for 48 h. The qPCR, patch-clamp, western blotting, immunostaining, dot blotting, bisulfite sequence, and overexpression of the ten-eleven translocation (TET) enzyme were performed for the study.

Results: After treated with cancer cell secretion, the maximum depolarization velocity and the action potential amplitude were reduced, the action potential duration prolonged, peak Na⁺ current, and the transient outward current were decreased, late Na⁺ and the slowly activating delayed rectifier K⁺ current were increased. Changes of mRNA and protein level of respective channels were detected along with altered DNA methylation level in CpG island in the promoter regions of ion channel genes and increased protein levels of DNA methyltransferases. Phosphoinositide 3-kinase (PI3K) inhibitor attenuated and transforming growth factor-β (TGF-β) mimicked the effects of cancer cell secretion.

Conclusions: GI cancer cell secretion could induce ion channel dysfunction, which may contribute to occurrence of arrhythmias in cancer patients. The ion channel dysfunction could result from DNA methylation of ion channel genes via activation of TGF-β/PI3K signaling. This study may provide new insights into pathogenesis of arrhythmia in cancer patients.

Keywords: DNA methylation; arrhythmia; cancer cell secretion; human-induced pluripotent stem cell-derived cardiomyocyte; ion channel.