MDR1 mediated chemoresistance: BMI1 and TIP60 in action.
Chemotherapy-induced emergence of drug resistant cells is frequently observed and is exemplified by the expression of family of drug resistance proteins including, multidrug resistance protein 1 (MDR1). However, a concise mechanism for chemotherapy-induced MDR1 expression is unclear. Mechanistically, mutational selection, epigenetic alteration, activation of the Wnt pathway or impaired p53 function have been implicated. The present study describes that the surviving fraction of cisplatin resistant cells co- upregulate MDR1, BMI1 and acetyl transferase activity of TIP60. Using complementary gain and loss of function approaches, we demonstrate that the expression of MDR1 is positively regulated by BMI1, a stem-cell factor classically known as a transcriptional repressor. Our study establishes a functional interaction between TIP60 and BMI-1 resulting in upregulation of MDR1 expression. Chromatin immunoprecipitation (ChIP) assays further establish that the proximal MDR1 promoter responds to cisplatin in a BMI1 dependent manner. BMI1 interacts with a cluster of E-box elements on the MDR1 promoter and recruits TIP60 resulting in acetylation of histone H2A and H3. Collectively, our data establish a hitherto unknown liaison among MDR1, BMI1 and TIP60 and provide mechanistic insights into cisplatin-induced MDR1 expression resulting in acquired cross-resistance against paclitaxel, doxorubicin and likely other drugs. In conclusion, our results advocate utilizing anti-BMI1 strategies to alleviate acquired resistance to chemotherapy.
Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Science Center, Oklahoma City, OK, USA; Department of Obstetrics and Gynecology, University of Oklahoma Health Science Center, Oklahoma City, OK, USA.
Soumyajit
S
Banerjee Mustafi
Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Science Center, Oklahoma City, OK, USA; Department of Pathology, University of Oklahoma Health Science Center, Oklahoma City, OK, USA.
Prabir Kumar
PK
Chakraborty
Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Science Center, Oklahoma City, OK, USA; Department of Obstetrics and Gynecology, University of Oklahoma Health Science Center, Oklahoma City, OK, USA.
Sarwat
S
Naz
Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Science Center, Oklahoma City, OK, USA; Department of Obstetrics and Gynecology, University of Oklahoma Health Science Center, Oklahoma City, OK, USA.
Shailendra Kumar Dhar
SK
Dwivedi
Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Science Center, Oklahoma City, OK, USA; Department of Obstetrics and Gynecology, University of Oklahoma Health Science Center, Oklahoma City, OK, USA.
Mark
M
Street
Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Science Center, Oklahoma City, OK, USA; Department of Obstetrics and Gynecology, University of Oklahoma Health Science Center, Oklahoma City, OK, USA.
Rumki
R
Basak
Center for Pharmacogenetics, Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA, USA; Women's Cancer Research Center, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA; Department of Computational & Systems Biology, University of Pittsburgh, Pittsburgh, PA, USA.
Da
D
Yang
Department of Biostatistics and Epidemiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
Kai
K
Ding
Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Science Center, Oklahoma City, OK, USA; Department of Pathology, University of Oklahoma Health Science Center, Oklahoma City, OK, USA.
Priyabrata
P
Mukherjee
Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Science Center, Oklahoma City, OK, USA; Department of Obstetrics and Gynecology, University of Oklahoma Health Science Center, Oklahoma City, OK, USA; Department of Cell Biology, University of Oklahoma College of Medicine, Oklahoma City, OK, USA.
Resham
R
Bhattacharya
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D000107:Acetylation / Q000187:drug effects; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D018432:Drug Resistance, Multiple / Q000187:drug effects* / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D051548:Histone Acetyltransferases / Q000235:genetics* / Q000378:metabolism; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D000074443:Lysine Acetyltransferase 5; D017239:Paclitaxel / Q000494:pharmacology; D063150:Polycomb Repressive Complex 1 / Q000819:agonists / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D015398:Signal Transduction
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D000970:Antineoplastic Agents; C069077:BMI1 protein, human; D006657:Histones; D004317:Doxorubicin; D051548:Histone Acetyltransferases; C098489:KAT5 protein, human; D000074443:Lysine Acetyltransferase 5; D063150:Polycomb Repressive Complex 1; D017239:Paclitaxel; D002945:Cisplatin
BMI1; Chemoresistance; MDR; TIP60