Forkhead box K2 modulates epirubicin and paclitaxel sensitivity through FOXO3a in breast cancer
File(s)
Published version
Author(s)
Lam, EW
Type
Journal Article
Abstract
The forkhead transcription factor FOXK2 has recently been implicated in cancer cell proliferation and survival, but a role in cancer
chemotherapeutic drug resistance has hitherto not been explored. Here we demonstrate that FOXK2 has a central role in mediating
the cytotoxic drug response in breast cancer. Clonogenic and cell viability assays showed that enhanced FOXK2 expression
sensitizes MCF-7 breast cancer cells to paclitaxel or epirubicin treatment, whereas FOXK2 depletion by small interfering RNAs
(siRNAs) confers drug resistance. Our data also showed that the activation of the tumour suppressor FOXO3a by paclitaxel and
epirubicin is mediated through the induction of FOXK2, as depletion of FOXK2 by siRNA limits the induction of FOXO3a by these
drugs in MCF-7 cells. Chromatin immunoprecipitation (ChIP) analysis showed that in response to drug treatment, FOXK2
accumulates and binds to the proximal FOXO3a promoter region in MCF-7 cells. Furthermore, we also uncovered that FOXK2 is
deregulated and, therefore, can express at high levels in the nucleus of both the paclitaxel and epirubicin drug-resistant MCF-7
cells. Our results showed that ectopically overexpressed FOXK2 accumulates in the nuclei of drug-resistant MCF-7 cells but failed to
be recruited to target genes, including FOXO3a. Crucially, we found that FOXO3a is required for the anti-proliferative and
epirubicin-induced cytotoxic function of FOXK2 in MCF-7 cells by sulphorhodamine and clonogenic assays. The physiological
importance of the regulation of FOXO3a by FOXK2 is further confirmed by the significant correlations between FOXO3a and FOXK2
expression in breast carcinoma patient samples. Further survival analysis also reveals that high nuclear FOXK2 expression
significantly associates with poorer clinical outcome, particularly in patients who have received conventional chemotherapy,
consistent with our finding that FOXK2 is deregulated in drug-resistant cells. In summary, our results suggest that paclitaxel and
epirubicin target the FOXK2 to modulate their cytotoxicity and deregulated FOXK2 confers drug resistance.
chemotherapeutic drug resistance has hitherto not been explored. Here we demonstrate that FOXK2 has a central role in mediating
the cytotoxic drug response in breast cancer. Clonogenic and cell viability assays showed that enhanced FOXK2 expression
sensitizes MCF-7 breast cancer cells to paclitaxel or epirubicin treatment, whereas FOXK2 depletion by small interfering RNAs
(siRNAs) confers drug resistance. Our data also showed that the activation of the tumour suppressor FOXO3a by paclitaxel and
epirubicin is mediated through the induction of FOXK2, as depletion of FOXK2 by siRNA limits the induction of FOXO3a by these
drugs in MCF-7 cells. Chromatin immunoprecipitation (ChIP) analysis showed that in response to drug treatment, FOXK2
accumulates and binds to the proximal FOXO3a promoter region in MCF-7 cells. Furthermore, we also uncovered that FOXK2 is
deregulated and, therefore, can express at high levels in the nucleus of both the paclitaxel and epirubicin drug-resistant MCF-7
cells. Our results showed that ectopically overexpressed FOXK2 accumulates in the nuclei of drug-resistant MCF-7 cells but failed to
be recruited to target genes, including FOXO3a. Crucially, we found that FOXO3a is required for the anti-proliferative and
epirubicin-induced cytotoxic function of FOXK2 in MCF-7 cells by sulphorhodamine and clonogenic assays. The physiological
importance of the regulation of FOXO3a by FOXK2 is further confirmed by the significant correlations between FOXO3a and FOXK2
expression in breast carcinoma patient samples. Further survival analysis also reveals that high nuclear FOXK2 expression
significantly associates with poorer clinical outcome, particularly in patients who have received conventional chemotherapy,
consistent with our finding that FOXK2 is deregulated in drug-resistant cells. In summary, our results suggest that paclitaxel and
epirubicin target the FOXK2 to modulate their cytotoxicity and deregulated FOXK2 confers drug resistance.
Date Issued
2015-09-07
Date Acceptance
2015-07-24
Citation
Oncogenesis, 2015, 4, pp.e167-e167
ISSN
2157-9024
Publisher
Nature Publishing Group
Start Page
e167
End Page
e167
Journal / Book Title
Oncogenesis
Volume
4
Copyright Statement
© 2015, Rights Managed by Nature Publishing Group. Oncogenesis is an open-access journal published by Nature Publishing
Group. This work is licensed under a Creative Commons Attribution 4.0
International License. The images or other third party material in this article are included
in the article’s Creative Commons license, unless indicated otherwise in the credit line; if
the material is not included under the Creative Commons license, users will need to
obtain permission from the license holder to reproduce the material. To view a copy of
this license, visit http://creativecommons.org/licenses/by/4.0/
Group. This work is licensed under a Creative Commons Attribution 4.0
International License. The images or other third party material in this article are included
in the article’s Creative Commons license, unless indicated otherwise in the credit line; if
the material is not included under the Creative Commons license, users will need to
obtain permission from the license holder to reproduce the material. To view a copy of
this license, visit http://creativecommons.org/licenses/by/4.0/
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Publication Status
Published