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.
|Number of pages||10|
|Journal||Breast Cancer Research and Treatment|
|State||Published - Nov 2010|
Bibliographical noteFunding Information:
Acknowledgments This study was supported by the grants from the Innovation Program of Shanghai Municipal Education Commission (No. 09ZZ04); the Natural Science Foundation of Shanghai (No. 09ZR1406900); and Shanghai Pujiang Program and Scientific Research Foundation for the Returned Overseas Chinese Scholars, State Education Ministry.
- Histone modification
- Multidrug resistance
ASJC Scopus subject areas
- Cancer Research