The Epigenome Analysis of the Mechanisms of Chemoresistance and Development new treatment in Rhabdoid Tumor
Description: Malignant rhabdoid tumor (MRT) is a highly aggressive pediatric cancer characterized by inactivation of SNF5, a core subunit of SWI/SNF complexes. Previously, we showed SNF5 contributes to transcriptional activation of NOXA, a pro-apoptotic protein that binds and inhibits the anti-apoptotic protein MCL-1. In this study, we found that NOXA expression was downregulated in both MRT cell lines and in clinical samples and that ectopically expressed NOXA bound MCL-1 and increased the sensitivity of MRT cell lines to doxorubicin (DOX) by promoting apoptosis. We also showed that knockdown of MCL-1 in MRT cell lines induced apoptosis and increased DOX sensitivity in MRT cells. Furthermore, we generate mice xenografts for both MCL-1 knockdown (KD) and control cell lines. We observed that mean tumor volume in the DOX-treated MCL-1 KD group was significantly smaller than that in the control group. Our results suggest that modulation of the NOXA/MCL-1 pathway underlies a chemoresistance in MRT.
Amount: ¥5,070,000
Funding type: research
Funder scheme: Grant-in-Aid for Scientific Research (C)
Start date: 2013-04-01
End date: 2016-03-31
Investigator: YASUMICHI KUWAHARA
Institution: Kyoto Prefectural University of Medicine
Funded outputs count: 3
Funder award ID: 25461602
OpenAlex ID: G801102498