TY - JOUR
T1 - CCAAT/Enhancer-binding protein delta mediates glioma stem-like cell enrichment and ATP-binding cassette transporter ABCA1 activation for temozolomide resistance in glioblastoma
AU - Wang, Shao Ming
AU - Lin, Wen Chi
AU - Lin, Hong Yi
AU - Chen, Yen Lin
AU - Ko, Chiung Yuan
AU - Wang, Ju Ming
N1 - Funding Information:
This work was supported by the grants MOST 107-2320-B-038-038 and MOST 108-2320-B-038-062-MY2 from the Ministry of Science and Technology, Taiwan. This work was also supported by the “TMU Research Center of Cancer Translational Medicine” from The Featured Areas Research Center Program within the framework of the Higher Education Sprout Project by the Ministry of Education (MOE) in Taiwan. Support was also provided by the National Institute on Drug Abuse, National Institutes of Health.
Publisher Copyright:
© 2021, The Author(s).
Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2021/6
Y1 - 2021/6
N2 - Glioblastoma (GBM) is the most aggressive brain tumor and relapses after chemo- or radiotherapy in a short time. The anticancer drug temozolamide (TMZ) is commonly used for GBM treatment, but glioma stem-like cells (GSCs) often lead to drug resistance and therapeutic failure. To date, the mechanism of GSC formation in TMZ-treated GBM remains largely unknown. CCAAT/Enhancer-binding protein delta (CEBPD) is an inflammation-responsive transcription factor and is proposed to be oncogenic in the context of drug resistance, prompting us to clarify its role in TMZ-resistant GBM. In this study, we first found that the CEBPD protein levels in GBM patients were significantly increased and further contributed to TMZ resistance by promoting GSC formation. Accordingly, the protein levels of stemness transcription factors, namely, SRY-box transcription factor 2 (SOX2), octamer-binding transcription factor 4 (OCT4), NANOG, and ATP-binding cassette subfamily A member 1 (ABCA1), were increased in GSCs and TMZ-treated GBM cells. Increased binding of CEBPD to promoter regions was observed in GSCs, indicating the direct regulation of these GSC-related genes by CEBPD. In addition, an ABCA1 inhibitor increased the caspase 3/7 activity of TMZ-treated GSCs, suggesting that TMZ efflux is controlled by ABCA1 activity and that the expression levels of the ABCA1 gene are an indicator of the efficiency of TMZ treatment. Together, we revealed the mechanism of CEBPD-mediated GSC drug resistance and proposed ABCA1 inhibition as a potential strategy for the treatment of TMZ-resistant GBM.
AB - Glioblastoma (GBM) is the most aggressive brain tumor and relapses after chemo- or radiotherapy in a short time. The anticancer drug temozolamide (TMZ) is commonly used for GBM treatment, but glioma stem-like cells (GSCs) often lead to drug resistance and therapeutic failure. To date, the mechanism of GSC formation in TMZ-treated GBM remains largely unknown. CCAAT/Enhancer-binding protein delta (CEBPD) is an inflammation-responsive transcription factor and is proposed to be oncogenic in the context of drug resistance, prompting us to clarify its role in TMZ-resistant GBM. In this study, we first found that the CEBPD protein levels in GBM patients were significantly increased and further contributed to TMZ resistance by promoting GSC formation. Accordingly, the protein levels of stemness transcription factors, namely, SRY-box transcription factor 2 (SOX2), octamer-binding transcription factor 4 (OCT4), NANOG, and ATP-binding cassette subfamily A member 1 (ABCA1), were increased in GSCs and TMZ-treated GBM cells. Increased binding of CEBPD to promoter regions was observed in GSCs, indicating the direct regulation of these GSC-related genes by CEBPD. In addition, an ABCA1 inhibitor increased the caspase 3/7 activity of TMZ-treated GSCs, suggesting that TMZ efflux is controlled by ABCA1 activity and that the expression levels of the ABCA1 gene are an indicator of the efficiency of TMZ treatment. Together, we revealed the mechanism of CEBPD-mediated GSC drug resistance and proposed ABCA1 inhibition as a potential strategy for the treatment of TMZ-resistant GBM.
UR - http://www.scopus.com/inward/record.url?scp=85099195355&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85099195355&partnerID=8YFLogxK
U2 - 10.1038/s41420-020-00399-4
DO - 10.1038/s41420-020-00399-4
M3 - Article
AN - SCOPUS:85099195355
SN - 2058-7716
VL - 7
JO - Cell Death Discovery
JF - Cell Death Discovery
IS - 1
M1 - 8
ER -