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Elevated HDAC activity and altered histone phospho-acetylation confer acquired radio-resistant phenotype to breast cancer cells

Authors
  • Sharda, Asmita1, 2
  • Rashid, Mudasir1, 2
  • Shah, Sanket Girish1, 2
  • Sharma, Ajit Kumar1, 3
  • Singh, Saurav Raj4
  • Gera, Poonam5
  • Chilkapati, Murali Krishna2, 4
  • Gupta, Sanjay1, 2
  • 1 Cancer Research Institute, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre (TMC), Kharghar, Navi Mumbai, MH, 410210, India , Navi Mumbai (India)
  • 2 Homi Bhabha National Institute, Training School Complex, Anushakti Nagar, Mumbai, MH, 400085, India , Mumbai (India)
  • 3 University of Alberta, 11560 University Avenue, Edmonton, Alberta, T6G 1Z2, Canada , Edmonton (Canada)
  • 4 Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre (TMC), Kharghar, Navi Mumbai, MH, 410210, India , Navi Mumbai (India)
  • 5 Biorepository, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre (TMC), Kharghar, Navi Mumbai, MH, 410210, India , Navi Mumbai (India)
Type
Published Article
Journal
Clinical Epigenetics
Publisher
Springer-Verlag
Publication Date
Jan 03, 2020
Volume
12
Issue
1
Identifiers
DOI: 10.1186/s13148-019-0800-4
Source
Springer Nature
Keywords
License
Green

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

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