Caspase-Dependent Cell Death and HDAC4 Translocation Following Microsecond Pulsed Electric Field (μsPEF) Exposure in MCF-7 Breast Cancer Cells

Abstract

Breast cancer is the second-leading cancer-related death among women. Survival rates decrease from 99% for localized stages of breast tumors to only 27% when distant metastases develop. Increased invasiveness and proliferation of breast cancer cells correlate with overexpression of an enzymatic coregulator of gene expression, histone deacetylase-4 (HDAC4). If HDAC4 is cleaved into two halves by another enzyme called caspase, one-half of HDAC4 goes into the nucleus of the cell where it promotes a highly regulated form of cellular self-destruction known as apoptosis. Caspases are activated by fast rises in calcium ion (Ca²⁺) concentrations inside cells, which can be initiated via plasma membrane electropermeabilization induced by microsecond pulsed electric fields (µsPEFs) applied to cells positioned between electrodes. However, the MCF-7 breast cancer cell line is deficient in caspase-3, which is the type of caspase predominantly responsible for cleavage of HDAC4. In this in vitro study, we demonstrate µsPEF exposure elicits HDAC4 translocation independently of caspase activity in MCF-7 cells. Yet, µsPEF-induced MCF-7 cell death remains dependent on Ca²⁺ electropermeabilization and caspase activity. Bioelectromagnetics. 00:00–00, 2025. © 2025 © 2025 Bioelectromagnetics Society.