Myocardin-related transcription factor A (MRTF-A) mediates doxorubicin-induced PERP transcription in colon cancer cells

Abstract

Doxorubicin (DOX) is a cytotoxic compound capable of instigating apoptosis in cancer cells. TP53 apoptosis effector (PERP) is a key mediator of apoptosis in multiple cell types. PERP transcription is activated by a range of pro-apoptotic stimuli. In the present study, we investigated the regulation of DOX-induced PERP transcription in colon cancer cells (SW480) by the transcriptional modulator myocardin-related transcription factor A (MRTF-A). We report that DOX treatment up-regulated MRTF-A expression paralleling PERP activation. DOX also promoted nuclear translocation of MRTF-A. On the contrary, MRTF-A depletion or inhibition attenuated DOX-induced apoptosis as evidenced by the MTT assay and caspase 3 cleavage. In accordance, MRTF-A depletion or inhibition dampened PERP transcription. Chromatin immunoprecipitation (ChIP) assay showed that DOX treatment promoted the binding of MRTF-A on the PERP promoter. Mechanistically, MRTF-A was recruited to the PERP promoter by activator protein 1 (AP-1). AP-1 interacted and cooperated with MRTF-A to activate PERP transcription. AP-1 silencing weakened PERP trans-activation by DOX presumably by compromising MRTF-A recruitment to the PERP promoter. In conclusion, our data suggest that MRTF-A might be a key regulator of DOX-induced PERP transcription in colon cancer cells.