UHRF1 inhibits MDR1 gene transcription and sensitizes breast cancer cells to anticancer drugs.
Overexpression of MDR1 in breast cancer remains a major cause for the failure of chemotherapy. In the present report, we find UHRF1 plays an important role in inhibiting MDR1 promoter activity by directly binding to the MDR1 promoter. Knockdown of UHRF1 activates MDR1 promoter activity and expression, attenuates the binding of UHRF1 and HDAC1 to the MDR1 promoter.Overexpression of UHRF1 in NCI/ADR-RES cells can induce deacetylation of histones H3 and H4 on the MDR1 promoter, which is facilitated by recruitment of HDAC1 to the MDR1 promoter. Loss of histone acetylation is accompanied by loss of binding of the key transcription factor, MyoD, CBP and p300, locking in marked suppression of MDR1, increasing sensitivity of MDR cancer cells to cytotoxic drugs that are transported by P-glycoprotein(P-gp). The inhibition of MDR1 expression by UHRF1 may provide potential ways to overcome multidrug resistance (MDR) in breast cancer treatment.
Jin
Wei
W
Department of Breast Surgery, Breast Cancer Institute, CancerHospital/Cancer Institute, Shanghai Medical College, Instituteof Biomedical Science, Fudan University, Shanghai 200032, People’s Republic of China.
Liu
Yang
Y
Xu
Si-guang
SG
Yin
Wen-jin
WJ
Li
Jun-jie
JJ
Yang
Jin-ming
JM
Shao
Zhi-ming
ZM
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D000107:Acetylation; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D019450:Genes, MDR; D006657:Histones / Q000378:metabolism; D006801:Humans; D008156:Luciferases; D049408:Luminescent Agents; D040081:Protein Array Analysis; D034741:RNA, Small Interfering / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic; D014162:Transfection; D014410:Tumor Stem Cell Assay; D044767:Ubiquitin-Protein Ligases; D015854:Up-Regulation
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D022762:CCAAT-Enhancer-Binding Proteins; D006657:Histones; D049408:Luminescent Agents; D034741:RNA, Small Interfering; D008156:Luciferases; C406364:UHRF1 protein, human; D044767:Ubiquitin-Protein Ligases