Abstract
BackgroundPoor-responsiveness of tumors to radiotherapy is a major clinical problem. Owing to the dynamic nature of the epigenome, the identification and targeting of potential epigenetic modifiers may be helpful to curb radio-resistance. This requires a detailed exploration of the epigenetic changes that occur during the acquirement of radio-resistance. Such an understanding can be applied for effective utilization of treatment adjuncts to enhance the efficacy of radiotherapy and reduce the incidence of tumor recurrence.ResultsThis study explored the epigenetic alterations that occur during the acquirement of radio-resistance. Sequential irradiation of MCF7 breast cancer cell line up to 20 Gy generated a radio-resistant model. Micrococcal nuclease digestion demonstrated the presence of compact chromatin architecture coupled with decreased levels of histone PTMs H3K9ac, H3K27 ac, and H3S10pK14ac in the G0/G1 and mitotic cell cycle phases of the radio-resistant cells. Further investigation revealed that the radio-resistant population possessed high HDAC and low HAT activity, thus making them suitable candidates for HDAC inhibitor–based radio-sensitization. Treatment of radio-resistant cells with HDAC inhibitor valproic acid led to the retention of γH2AX and decreased H3S10p after irradiation. Additionally, an analysis of 38 human patient samples obtained from 8 different tumor types showed variable tumor HDAC activity, thus demonstrating inter-tumoral epigenetic heterogeneity in a patient population.ConclusionThe study revealed that an imbalance of HAT and HDAC activities led to the loss of site-specific histone acetylation and chromatin compaction as breast cancer cells acquired radio-resistance. Due to variation in the tumor HDAC activity among patients, our report suggests performing a prior assessment of the tumor epigenome to maximize the benefit of HDAC inhibitor–based radio-sensitization.Graphical abstract
Highlights
IntroductionOwing to the dynamic nature of the epigenome, the identification and targeting of potential epigenetic modifiers may be helpful to curb radio-resistance
Poor-responsiveness of tumors to radiotherapy is a major clinical problem
Radio-resistant cells display alterations of various physiological processes MCF7 breast cancer cell line was subjected to radiation (10 rounds of 2 Gy each) and a radio-resistant sub-cell line was generated (Fig. 1a)
Summary
Owing to the dynamic nature of the epigenome, the identification and targeting of potential epigenetic modifiers may be helpful to curb radio-resistance This requires a detailed exploration of the epigenetic changes that occur during the acquirement of radio-resistance. Attempts to elucidate the genetic, proteomic and transcriptomic determinants of radio-resistance revealed altered gene expression patterns and protein– protein interaction networks [6,7,8,9]. These studies have a major caveat of not taking the cell cycle phase–specific alterations in gene expression and protein profile into consideration. Identification of specific radio-resistance-associated signature patterns can be of immense utility to develop novel treatment strategies or introduce “customized” radio-sensitizers to prevent recurrence [13]
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