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Volume 27
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10.3390/ijms27156649
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This is an early access version, the complete PDF, HTML, and XML versions will be available soon.
Review

A Convergence Model of Bioelectric, Gap Junctional, and Hippo–YAP Signalling in Oral Cancer Stem Cell Maintenance

by
Surendra Kumar Acharya
1,*,†,
Wei Cheong Ngeow
1,
Firdaus Hariri
1,
Fong Fong Liew
2 and
Yee Fan Choon
3,†
1
Department of Oral and Maxillofacial Clinical Sciences, Faculty of Dentistry, University of Malaya, Kuala Lumpur 50603, Malaysia
2
Department of Pharmaceutical Life Sciences, Faculty of Pharmacy, University of Malaya, Kuala Lumpur 50603, Malaysia
3
Department of Pediatric Dentistry, Faculty of Dental Medicine, Universitas Airlangga, Surabaya 60132, Indonesia
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Int. J. Mol. Sci. 2026, 27(15), 6649; https://doi.org/10.3390/ijms27156649
Submission received: 30 May 2026 / Revised: 20 July 2026 / Accepted: 23 July 2026 / Published: 25 July 2026
(This article belongs to the Special Issue Cancer Stem Cells: Molecular Mechanisms and Therapeutic Targeting)
Versions Notes

Abstract

Cancer stem cell (CSC) persistence drives recurrence and therapy resistance in oral squamous cell carcinoma (OSCC), but what keeps cells locked in this stem-like state is poorly understood. In this narrative review, we propose that CSC state is sustained not by any single pathway but by joint dysregulation of three interacting cell-biological systems: membrane potential (Vmem), communication between neighbouring cells through gap junctional intercellular communication (GJIC), and the Hippo–YAP pathway. We argue that these systems act together on one common point—the YAP protein, retained in the nucleus—which switches on a SOX2-centred stemness gene programme and stabilises a self-reinforcing CSC state. Drawing on evidence from cancer genomics, developmental bioelectricity, connexin biology, and OSCC-specific studies, we reconstruct how membrane depolarisation, loss of gap junction coupling, FAT1 mutation, and Hippo pathway inactivation could converge on persistent nuclear YAP, and how betel quid—the principal risk factor across South and Southeast Asia—may engage all three systems at once. Because the model holds that each input reinforces the others, it predicts that targeting several together should displace CSC state more durably than targeting any one alone. We set out the testable predictions this framework generates.
Keywords: bioelectric signalling; cancer stem cells; FAT1; gap junctional intercellular communication; Hippo–YAP signalling; oral squamous cell carcinoma; oral submucous fibrosis bioelectric signalling; cancer stem cells; FAT1; gap junctional intercellular communication; Hippo–YAP signalling; oral squamous cell carcinoma; oral submucous fibrosis

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MDPI and ACS Style

Acharya, S.K.; Ngeow, W.C.; Hariri, F.; Liew, F.F.; Choon, Y.F. A Convergence Model of Bioelectric, Gap Junctional, and Hippo–YAP Signalling in Oral Cancer Stem Cell Maintenance. Int. J. Mol. Sci. 2026, 27, 6649. https://doi.org/10.3390/ijms27156649

AMA Style

Acharya SK, Ngeow WC, Hariri F, Liew FF, Choon YF. A Convergence Model of Bioelectric, Gap Junctional, and Hippo–YAP Signalling in Oral Cancer Stem Cell Maintenance. International Journal of Molecular Sciences. 2026; 27(15):6649. https://doi.org/10.3390/ijms27156649

Chicago/Turabian Style

Acharya, Surendra Kumar, Wei Cheong Ngeow, Firdaus Hariri, Fong Fong Liew, and Yee Fan Choon. 2026. "A Convergence Model of Bioelectric, Gap Junctional, and Hippo–YAP Signalling in Oral Cancer Stem Cell Maintenance" International Journal of Molecular Sciences 27, no. 15: 6649. https://doi.org/10.3390/ijms27156649

APA Style

Acharya, S. K., Ngeow, W. C., Hariri, F., Liew, F. F., & Choon, Y. F. (2026). A Convergence Model of Bioelectric, Gap Junctional, and Hippo–YAP Signalling in Oral Cancer Stem Cell Maintenance. International Journal of Molecular Sciences, 27(15), 6649. https://doi.org/10.3390/ijms27156649

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