Histone Deacetylase Inhibitors orchestrate epigenetic signalling and alter the nucleoporins and nuclear envelope in cervical cancer

Abstract

Histone Deacetylases inhibitors (HDACi) modulate the acetylation profile of lysines on the histone tails to facilitate DNA accessibility to transcription factors. While the phenotypes caused by HDAC inhibition on cancer cells have been studied extensively, the nuclear geometry and expression signatures modulated by these enzymes have not been well understood.This work attempts to understand the functional implication of HDAC inhibitor treatment (NaB and MS275) on cervical cancer cells. We observed an increase in nuclear area upon HDAC inhibition correlating with an increase in expression of active histone marks and lamins and a decrease in levels of repressive epigenetic marks. Our transcriptomic sequencing of HeLa cells treated individually with these inhibitors have identified dysregulation of nucleoporins affecting the nucleocytoplasmic exchange and nucleo-cytoplasmic transport through the nuclear pores. These act in concert with the increase in acetylation due to HDAC inhibition and contribute to the increase in nuclear area. In order to derive clinical implications of the observed mechano signalling genes and epigenetic factors differentially expressed in HeLa cells, we verified these on a TCGA cervical cancer cohort of 148 patients and observed an upregulation of various nucleoporins in cervical cancer patients. Interestingly, the low expression of LMNA and high expression of NUP58 were associated with lower survival rate in the cohort. These signatures have also been validated on Indian cervical cancer tissues. This novel and intricate mechanism of modulating epigenetic regulation and nuclear architecture changes by HDAC inhibition can be utilized for designing targetted epigenetic therapy for cervical cancer.