Potential of Microsecond Pulse Electric Fields (µsPEF) for Epigenetic Manipulation and Breast Cancer Treatment

Microsecond pulsed electric fields (µsPEF) have the potential to treat cancer by initiating biochemical cascades. Cell death is induced by electroporation leading to imbalanced intracellular ion concentrations, such as [Ca²⁺] [1-3]. When each binding site of Ca²⁺-dependent protein, calmodulin, is saturated with Ca²⁺, calmodulin undergoes a conformational change that permits it to interact with and activate a diverse set of enzymes, especially the kinase CaMKII [4], which act further downstream. If cell death is not initiated by msPEF exposure, perhaps exposed cells respond via (in)activation of other signaling pathways. For example, CaMKII phosphorylates histone deacetylases such as HDAC4, causing export of HDAC4 from the nucleus – thereby disrupting its role in genetic transcription and regulation. Thus, proliferation, growth and development of breast cancer cells can be “switched off” [5,6].

In this study, we stimulated nucleocytoplasmic shuttling of HDAC4 in MCF7 cells by applying 300 V for 100 ms with varying numbers of square-wave pulses (1, 10, or 50) at 1 Hz repetition rate. We postulate that increased Ca²⁺ uptake due to msPEF exposure activated calmodulin and CaMKII, leading to HDAC4 translocation outside nuclei. Disruption of proliferation of MCF7 breast cancer cells was manipulated via msPEF exposure-induced inhibition of HDAC4.

References

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[2] Cemazar, M et al., Electro- Magnetobiol, 1998; 17:263-272.

[3] Thompson, GL et al., J Biomed Opt, 2014; 19:055005.

[4] Prevarskaya, N et al., Phil Trans R Soc B, 2014; 369:20130097.

[5] Backs, J et al., Mol Cell Biol, 2008; 28(10):3437-3445.

[6] Li, Y and E Seto, Cold Spring Harb Perspect Med 2016:a026831.