CBP-dependent Wnt/β-catenin signaling is crucial in regulation of MDR1 transcription
Aberrant expression of the MDR1-encoded P-glycoprotein (P-gp) is often associated with clinical multi-drug
resistance (MDR) leading to poor prognosis and failure of chemotherapy. However, the precise and cooperative molecular
mechanism responsible for MDR1 transcription and expression in acquired MDR remains elusive. We, herein,
demonstrate that Wnt/β-catenin signal pathway is constitutively activated in Doxorubicin-induced MDR cancer cells, in
which nuclear β -catenin specifically interacts with the transcriptional coactivator CBP in a MEK1/2/ERK1/2 signaldependent
manner. Specific knockdown of both β-catenin and CBP by RNAi-mediated depletion abrogates MDR1
transcription and expression resulting in a complete reversal of P-gp-dependent efflux function and restoration of
sensitivity to the Doxorubincin-induced cytotoxicity. Moreover, following pharmacological disruption of CBP and β -
catenin interaction through inhibition of the MEK1/2/ERK1/2 signal by the specific inhibitor PD98059, MDR1 transcription
and its encoded P-gp-dependent function are abolished. These findings conclude that the CBP/β-catenin complex is a
core component of the MDR1 transcriptional “enhancesome”.
Keywords: CBP, Chromatin Immunoprecipitation, MDR1, p300, RNAi, Wnt/β-catenin.
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