Doxorubicin enhances Snail/LSD1-mediated PTEN suppression in a PARP1-dependent manner

Yiwei Lin, Tiebang Kang, Binhua P. Zhou

Research output: Contribution to journalArticlepeer-review

31 Scopus citations


The transcription factor Snail not only functions as a master regulator of epithelial-mesenchymal transition (EMT), but also mediates cell proliferation and survival. While previous studies have showed that Snail protects tumor cells from apoptosis through transcriptional repression of PTEN, the specific mechanism remains unclear. In this study, we demonstrated that Snail cooperates with LSD1 to repress PTEN in a PARP1-dependent manner. Upon doxorubicin treatment, Snail becomes tightly associated with PARP1 through its pADPr-binding motif and is subject to poly(ADP-ribosyl)ation. This modification can enhance Snail-LSD1 interaction and promote the recruitment of LSD1 to PTEN promoter, where LSD1 removes methylation on histone H3 lysine 4 for transcription repression. Furthermore, treatment of tumor cells with PARP1 inhibitor AZD2281 can compromise doxorubicin-induced PTEN suppression and enhance the inhibitory effect of doxorubicin. Together, we proposed a tentative drug-resistant mechanism through which tumor cells defend themselves against DNA damage-induced apoptosis. PARP1 inhibitors in combination with DNA damaging reagents might represent a promising treatment strategy targeting tumors with over-activated Snail and LSD1.

Original languageEnglish
Pages (from-to)1708-1716
Number of pages9
JournalCell Cycle
Issue number11
StatePublished - Jun 1 2014

Bibliographical note

Funding Information:
This work was supported by grants from NIH (2CA125454), an Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health under grant number P20 GM103527-06 (to B.P.Z), and pre-doctoral fellowship (BC101068) from DoD Breast Cancer Research Program (to Y.L.).


  • LSD1
  • PARP1
  • PTEN
  • Poly(ADP-ribosyl)ation
  • Snail

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology
  • Cell Biology


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