FOXM1 contributes to taxane resistance by regulating UHRF1-controlled cancer cell stemness

Yuan, Bowen; Liu, Youhong; Yu, Xiaohui; Yin, Linglong; Peng, Yuchong; Gao, Yingxue; Zhu, Qianling; Cao, Tuoyu; Yang, Yinke; Fan, Xue‐Gong; Li, Xiong

doi:10.1038/s41419-018-0631-9

Cited by 49 publications

(45 citation statements)

References 38 publications

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“…Moreover, the resistance to docetaxel on invasion in the resistant cells could be partially reversed through siRNA-mediated FOXM1 inhibition. These data are consistent with the previous studies which revealed that overexpression or downregulation of FOXM1 could significantly modulate the effects of multiple chemotherapeutic drugs on cell migration and invasion [8][9][10][11][12]. These data confirm the oncogenic role of FOXM1 in the maintenance of the tumor invasion and metastasis.…”

Section: Discussionsupporting

confidence: 93%

“…Recent studies have demonstrated that FOXM1 is frequently overexpressed in different kinds of cancers, including PCa, and is confirmed to be highly correlated with the proliferation and metastasis of many cancers [3][4][5][6][7]. Moreover, several studies indicated that FOXM1 overexpression conferred acquired chemotherapy tolerance through the regulation of many genes, including ATP-binding cassette genes [8][9], DNA damage repair genes [10], apoptosis-associated genes [11], cancer stem cell-related genes [12][13], and so on.…”

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confidence: 99%

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FOXM1 modulates docetaxel resistance in prostate cancer by regulating KIF20A

Yu¹,

Xu²,

wang

et al. 2020

Preprint

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Background Resistance to docetaxel is an important factor which affects the prognosis in advanced prostate cancer (PCa). The precise mechanisms remain unclear. The transcription factor Forkhead box M1 (FOXM1), participating in cell cycle progress and cell proliferation, has been reported to affect the sensitivity of chemotherapy. The present study aims to explore the role of FOXM1 in docetaxel resistance of PCa and how FOXM1 is associated with kinesin family member 20 A (KIF20A), which has been demonstrated to promote the development of therapeutic resistance in some cancers. Methods:We monitored cell growth by MTT and colony formation assays and cell apoptosis and cell cycle through flow cytometry. Wound-healing and transwell assays were performed to detect cell migration and invasion. Gene expression was analyzed by quantitative reverse transcription polymerase chain reaction (RT-qPCR) and western blotting. We determined the binding of FOXM1 on the KIF20A promoter by the ChIP assay. Tumorigenicity in nude mice was employed to assess tumorigenicity in vivo. Results: FOXM1 knockdown induced cell apoptosis and G2/M cell cycle arrest while hampered cell migration and invasion in docetaxel-resistant PCa cell lines (DU145-DR and VCaP-DR). The opposite trend was found in their parental cells with exogenous FOXM1 overexpression. Furthermore, thiostrepton, a specific inhibitor for FOXM1, significantly attenuated docetaxel resistance in vitro and in vivo. Additionally, we found that FOXM1 and KIF20A were consistently overexpressed and highly correlated in PCa cells and tissues. Further studies demonstrated that FOXM1 regulated the expression of KIF20A at the transcriptional level directly through a Forkhead response element (FHRE) in its promoter. Moreover, KIF20A overexpression could partially reverse the effects of FOXM1 depletion on cell proliferation, cell cycle proteins (cyclinA2, cyclinD1 and cyclinE1) and apoptosis protein (Bcl-2 and PARP).Conclusions: our findings suggest that FOXM1 may promote docetaxel resistance partly through the induction of KIF20A expression and provide insights into novel chemotherapeutic strategies for docetaxel resistance in PCa. Cell lines and culturesProstate cancer cell lines DU145 and VCaP were purchased from the Chinese Academy of Sciences, Shanghai Institute of Biochemistry and Cell Biology (Shanghai, China). These cells were maintained at 37 ˚C with 5% CO2 in an RPMI-1640 and DMEM culture medium, respectively, containing 10% fetal bovine serum and 1% streptomycin/penicillin. The docetaxel resistant cell line DU145-DR and VCaP-DR were developed by the methods as described in our previous publication [15]. TransfectionThe sequences of siRNAs of FOXM1 and KIF20A were as follows: the sense sequence of siRNA FOXM1: 5′-CUCUUCUCCCUCAGAUAUATT-3′, and the antisense sequence: 5′-UAUAUGAGGGAGAGTT-3′; the sense sequence of siRNA KIF20A: 5′-GCAGCAGGUUCCAUCUGAGTT-3′, and the antisense sequence: 5′-CUCAGAUGG AACCUGCUGCTT-3′. The sequence of non-targeting control siRNA is the 5′-UUCUCCGAACGUGUCAC...

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Section: Discussionsupporting

confidence: 93%

mentioning

confidence: 99%

FOXM1 modulates docetaxel resistance in prostate cancer by regulating KIF20A

Yu¹,

Xu²,

wang

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…Moreover, the docetaxel resistance of invading cells could be partially reversed through siRNA-mediated FOXM1 inhibition. These data are consistent with the previous studies which revealed that overexpression or downregulation of FOXM1 could signi cantly modulate the effects of multiple chemotherapeutic drugs on cell migration and invasion [9][10][11][12][13]. These data con rm the oncogenic role of FOXM1 in the maintenance of the tumor invasion and metastasis.…”

Section: Discussionsupporting

confidence: 92%

“…Recent studies have demonstrated that FOXM1 is frequently overexpressed in different kinds of cancers, including PCa, and is con rmed to be highly correlated with the proliferation and metastasis of many cancers [4][5][6][7][8]. Moreover, several studies indicated that FOXM1 overexpression conferred acquired chemotherapy tolerance through the regulation of many genes, including ATP-binding cassette genes [9][10], DNA damage repair genes [11], apoptosis-associated genes [12], cancer stem cell-related genes [13][14], and so on. In our previous study, we reported that FOXM1 overexpression can signi cantly reduce the inhibitory effect of docetaxel on cell proliferation in PCa by inducing autophagy [15].…”

Section: Introductionmentioning

confidence: 99%

FOXM1 modulates docetaxel resistance in prostate cancer by regulating KIF20A

Yu¹,

Xu²,

wang

et al. 2020

Preprint

View full text Add to dashboard Cite

Background：Resistance to docetaxel is an important factor which affects the prognosis in advanced prostate cancer (PCa). The precise mechanisms remain unclear. The transcription factor Forkhead box M1 (FOXM1), participating in cell cycle progress and cell proliferation, has been reported to affect the sensitivity of chemotherapy. The present study aims to explore the role of FOXM1 in docetaxel resistance of PCa and how FOXM1 is associated with kinesin family member 20 A (KIF20A), which has been demonstrated to promote the development of therapeutic resistance in some cancers. Methods: We monitored cell growth by MTT and colony formation assays , and cell apoptosis and cell cycle through flow cytometry. Wound-healing and transwell assays were performed to detect cell migration and invasion. The mRNA and protein expression of gene were analyzed by by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and western blotting, respectively. We determined the binding of FOXM1 on the KIF20A promoter by the ChIP assay. Tumorigenicity in nude mice was employed to assess tumorigenicity in vivo. Results: FOXM1 knockdown induced cell apoptosis and G2/M cell cycle arrest, and suppressed cell migration and invasion in docetaxel-resistant PCa cell lines (DU145-DR and VCaP-DR). The opposite trend was found in their parental cells with exogenous FOXM1 overexpression. Furthermore, thiostrepton, a specific inhibitor for FOXM1, significantly attenuated docetaxel resistance in vitro and in vivo. Additionally, we found that FOXM1 and KIF20A were consistently overexpressed and highly correlated in PCa cells and tissues. Further studies demonstrated that FOXM1 regulated the expression of KIF20A at the transcriptional level directly through a Forkhead response element (FHRE) in its promoter. Moreover, KIF20A overexpression could partially reverse the effects of FOXM1 depletion on cell proliferation, cell cycle proteins (cyclinA2, cyclinD1 and cyclinE1) and apoptosis protein (bcl-2 and PARP). Conclusions: our findings suggest that highly expressed FOXM1 may promote docetaxel resistance partly through the induction of KIF20A expression and provide insights into novel chemotherapeutic strategies for docetaxel resistance in PCa.

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“…As we mentioned above, there are a number of mechanisms proposed to illuminate the development of docetaxel resistance, for instance, altered tumor microenvironment, 32 drug efflux genes, 33 cancer stem cells, 34 antiapoptotic mechanism, 35 and so on. Besides these, aberrant AR might be a critical factor in drug resistance 36 .…”

Section: Discussionmentioning

confidence: 99%

Docetaxel suppresses immunotherapy efficacy of natural killer cells toward castration‐resistant prostate cancer cells via altering androgen receptor‐lectin‐like transcript 1 signals

et al. 2020

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Background: Docetaxel is an effective first-line chemotherapy agent used in the treatment of castration-resistant prostate cancer (CRPC) patients. However, most times chemotherapy with docetaxel eventually fails due to the development of docetaxel resistance. Natural killer (NK) cells are the first line of defense against cancer and infections. NK cell function is determined by a delicate balance between signals received via activating and inhibitory receptors. The aim of this study is to explore whether the potential docetaxel-resistant mechanism is associated with impaired NK cell cytotoxicity toward CRPC cells.Methods: By performing MTT assay, we explored the role of docetaxel in regulating NK cells' cytotoxicity. Western blot and quantitative real-time polymerase chain reaction analysis were used to measure messenger RNA and protein levels separately. Luciferase reporter assay and chromatin immunoprecipitation assay were performed to analyze the mechanism.Results: We found that docetaxel could suppress the immunotherapy efficacy of NK cells toward CRPC cells via the androgen receptor (AR)-lectin-like transcript 1 (LLT1) signals in vitro. Analysis of the mechanism revealed that docetaxel functioned through increasing AR to upregulate LLT1 expression in CRPC cells. AR transcriptionally activated LLT1 expression by binding to its promoter region. Furthermore, targeting AR with ASC-J9 or blocking LL1 by anti-human LLT1 monoclonal antibody could reverse the suppressive effect of docetaxel on the immunotherapy efficacy of NK cells toward CRPC cells. Conclusions:We concluded that chemotherapy agent docetaxel could increase AR that transcriptionally regulated the expression of NK inhibitory ligand LLT1 on CRPC cells. An increase of LL1 may further suppress the immunological efficacy of NK cells to kill CRPC cells. Additionally, targeting AR or blocking LL1 could enhance the immunotherapy efficacy of NK cells toward CRPC cells which might be Min Tang, Shenglin Gao, and Lei Zhang contributed equally to this study.

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FOXM1 contributes to taxane resistance by regulating UHRF1-controlled cancer cell stemness

Cited by 49 publications

References 38 publications

FOXM1 modulates docetaxel resistance in prostate cancer by regulating KIF20A

FOXM1 modulates docetaxel resistance in prostate cancer by regulating KIF20A

FOXM1 modulates docetaxel resistance in prostate cancer by regulating KIF20A

Docetaxel suppresses immunotherapy efficacy of natural killer cells toward castration‐resistant prostate cancer cells via altering androgen receptor‐lectin‐like transcript 1 signals

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