DNA methylation of the Oct4A enhancers in embryonal carcinoma cells after etoposide treatment is associated with alternative splicing and altered pluripotency in reversibly senescent cells

Mikhail Baryshev, Inna Inashkina, Kristine Salmina, Anda Huna, Thomas R. Jackson, Jekaterina Erenpreisa

Research output: Contribution to journalArticlepeer-review

7 Citations (Scopus)

Abstract

The epigenetic mechanisms underlying chemoresistance in cancer cells resulting from drug-induced reversible senescence are poorly understood. Chemoresistant ESC-like embryonal carcinoma PA1 cells treated with etoposide (ETO) were previously found to undergo prolonged G2 arrest with transient p53-dependent upregulation of opposing fate regulators, p21CIP1 (senescence) and OCT4A (self-renewal). Here we report on the analysis of the DNA methylation state of the distal enhancer (DE) and proximal enhancer (PE) of the Oct4A gene during this dual response. When compared to non–treated controls the methylation level increased from 1.3% to 12.5% and from 3% to 19.4%, in the DE and PE respectively. It included CpG and non-CpG methylation, which was not chaotic but presented two patterns in each enhancer. Discorrelating with methylation of enhancers, the transcription of Oct4A increased, however, a strong expression of the splicing form Oct4B was also induced, along with down-regulation of the Oct4A partners of in the pluripotency/self-renewal network Sox2 and Lin28. WB demonstrated disjoining of the OCT4A protein from the chromatin-bound fraction. In survival clones, methylation of the DE was considerably erased, while some remnant of methylation of the PE was still observed. The alternative splicing for Oct4B was reduced, Oct4A level insignificantly decreased, while the expression of Sox2 and Lin28 recovered, all three became proportionally above the control. These findings indicate the involvement of the transient patterned methylation of the Oct4A enhancers and alternative splicing in the adaptive regulation of cell fate choice during the p53-dependant dual state of reversible senescence in ESC-like cancer stem cells.

Original languageEnglish
Pages (from-to)362-366
Number of pages5
JournalCell Cycle
Volume17
Issue number3
DOIs
Publication statusPublished - 1 Feb 2018

Keywords

  • alternative splicing
  • cell senescence
  • DNA damage
  • embryonal carcinoma
  • enhancer methylation
  • Oct4A
  • transient pluripotency suppression
  • wt TP53

Field of Science

  • 3.2 Clinical medicine

Publication Type

  • 1.1. Scientific article indexed in Web of Science and/or Scopus database

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