title: Doxorubicin enhances Snail/LSD1-mediated PTEN suppression in a PARP1-dependent manner.
abstract: 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.
authors.affiliation: Departments of Molecular and Cellular Biochemistry and Markey Cancer Center; University of Kentucky College of Medicine; Lexington, KY USA.
authors.forename: Yiwei
authors.initials: Y
authors.lastname: Lin
authors.affiliation: Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China and Collaborative Innovation Center of Cancer Medicine; Guangzhou, China.
authors.forename: Tiebang
authors.initials: T
authors.lastname: Kang
authors.affiliation: Departments of Molecular and Cellular Biochemistry and Markey Cancer Center; University of Kentucky College of Medicine; Lexington, KY USA; Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China and Collaborative Innovation Center of Cancer Medicine; Guangzhou, China.
authors.forename: Binhua P
authors.initials: BP
authors.lastname: Zhou
mesh_terms: D015153:Blotting, Western; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D019175:DNA Methylation / Q000235:genetics; D004317:Doxorubicin / Q000494:pharmacology*; D004591:Electrophoresis, Polyacrylamide Gel; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D057809:HEK293 Cells; D056466:Histone Demethylases / Q000378:metabolism*; D006801:Humans; D051059:PTEN Phosphohydrolase / Q000037:antagonists & inhibitors*; D010793:Phthalazines; D010879:Piperazines; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D000071250:Snail Family Transcription Factors; D013778:Tetrazolium Salts; D013844:Thiazoles; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D010793:Phthalazines; D010879:Piperazines; D000071250:Snail Family Transcription Factors; D013778:Tetrazolium Salts; D013844:Thiazoles; D014157:Transcription Factors; D004317:Doxorubicin; D056466:Histone Demethylases; C495195:KDM1A protein, human; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; C022616:thiazolyl blue; C531550:olaparib
keywords: LSD1; PARP1; PTEN; Snail; poly(ADP-ribosyl)ation