High FOXM1 expression is a prognostic marker for poor clinical outcomes in prostate cancer

Kim, Mee Young; Jung, Ae Ryang; Kim, Ga Eun; Yang, Jonghyup; Ha, U-Syn; Hong, Seok-In; Choi, Yeong Jin; Moon, Myung Sang; Kim, Sae Woong; Lee, Ji Youl; Park, Yong Hyun

doi:10.7150/jca.28099

Cited by 30 publications

(24 citation statements)

References 29 publications

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“…Several studies indicated that the development of docetaxel resistance was associated with upregulation of FOXM1, which could be reversed by down-regulating FOXM1 expression in some cancers [12,[19][20][21]. A recent study has revealed that high FOXM1 expression is associated with advanced PCa stages, high gleason score, and poor prognosis [22]. In our study, we found that the FOXM1 level signi cantly increased along with the development of acquired resistance in PCa.…”

Section: Discussionsupporting

confidence: 60%

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. 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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Section: Discussionsupporting

confidence: 60%

FOXM1 modulates docetaxel resistance in prostate cancer by regulating KIF20A

Yu¹,

Xu²,

wang

et al. 2020

Preprint

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“…Furthermore, FOXM1 has been observed to drive prostate cancer metastasis or malignancy by forming the COUP–TFII–FOXM1–CENPF cascade [ 48 ] or by cooperating with CENPF [ 49 ]. Importantly, high FOXM1 expression level has been correlated with advanced tumor stages, high Gleason score, and poor prognosis [ 50 ]. Accordingly, targeting the FOXM1 pathway using the novel inhibitor Monensin is considered as an efficient therapeutic strategy for mCRPC [ 33 ].…”

Section: Discussionmentioning

confidence: 99%

SETD1A Promotes Proliferation of Castration-Resistant Prostate Cancer Cells via FOXM1 Transcription

Yang

Jin

Park

et al. 2020

Cancers

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Androgen deprivation therapy eventually leads to the development of castration-resistant prostate cancer (CRPC). Here, we demonstrate for the first time that the histone H3K4 methyltransferase SETD1A is a major regulator for the proliferation of metastatic CRPC (mCRPC). The expression of SETD1A was significantly correlated with the survival rate of patients with prostate cancer. SETD1A, which is expressed at a higher level in mCRPC than in primary prostate cancer cells, promotes the expression of FOXM1, a gene encoding a cell proliferation-specific transcription factor. SETD1A is recruited to the promoter region of FOXM1 (forkhead box M1) upon binding to E2F1, a protein that regulates the transcription of FOXM1 and contributes to the trimethylation of H3K4 in the FOXM1 promoter region. In addition, SETD1A is essential for the expression of stem cell factor (e.g., OCT4, octamer-binding transcription factor 4) and stem cell formation in mCRPC, suggesting the importance of SETD1A expression in mCRPC tumor formation. Notably, poor prognosis is associated with high expression of the SETD1A–FOXM1 pair in clinical data sets. Therefore, our study suggests that SETD1A plays an important role in the proliferation of mCRPC by regulating FOXM1 transcription.

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“…FOXM1 (Forkhead box M1) functions as a transcriptional factor to regulate expression of proliferation-associated genes and participates in DNA replication and mitosis [21]. FOXM1 has been shown to regulate cell cycle during progression of prostate cancer [22], breast cancer [23], colorectal cancer [24] and RCC [25]. More interestingly, OTUB1 was shown to promote deubiquitination of FOXM1 in breast cancer [26] and ovarian cancer [27] to facilitate tumor progression.…”

Section: Introductionmentioning

confidence: 99%

OTUB1-mediated deubiquitination of FOXM1 up-regulates ECT-2 to promote tumor progression in renal cell carcinoma

et al. 2020

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Background: OTUB1 (ovarian tumor domain protease domain-containing ubiquitin aldehyde-binding proteins)mediated deubiquitination of FOXM1 (Forkhead box M1) participates in carcinogenesis of various tumors. We aim to investigate the effect and mechanism of OTUB1/FOXM1 on RCC (renal cell carcinoma) progression. Expression levels of OTUB1 in RCC tissues and cell lines were examined by qRT-PCR (quantitative real-time polymerase chain reaction) and immunohistochemistry. Cell proliferation was measured with CCK8 (Cell Counting Kit-8) and colony formation assays. Wound healing and transwell assays were used to determine cell migration and invasion, respectively. The effect of OTUB1 on FOXM1 ubiquitination was examined by Immunoprecipitation. Western blot was used to uncover the underlying mechanism. In vivo subcutaneous xenotransplanted tumor model combined with immunohistochemistry and western blot were used to examine the tumorigenic function of OTUB1. Results: OTUB1 was up-regulated in RCC tissues and cell lines, and was associated with poor prognosis of RCC patients. Knockdown of OTUB1 inhibited cell viability and proliferation, as well as migration and invasion of RCC cells. Mechanistically, knockdown of OTUB1 down-regulated FOXM1 expression by promoting its ubiquitination. Downregulation of FOXM1 inhibited ECT2 (epithelial cell transforming 2)-mediated Rho signaling. Moreover, the inhibition of RCC progression caused by OTUB1 knockdown was reversed by FOXM1 over-expression. In vivo subcutaneous xenotransplanted tumor model also revealed that knockdown of OTUB1 could suppress in vivo RCC growth via downregulation of FOXM1-mediated ECT2 expression. Conclusions: OTUB1-mediated deubiquitination of FOXM1 up-regulates ECT-2 to promote tumor progression in RCC, providing a new potential therapeutic target for RCC treatment.

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High FOXM1 expression is a prognostic marker for poor clinical outcomes in prostate cancer

Cited by 30 publications

References 29 publications

FOXM1 modulates docetaxel resistance in prostate cancer by regulating KIF20A

FOXM1 modulates docetaxel resistance in prostate cancer by regulating KIF20A

SETD1A Promotes Proliferation of Castration-Resistant Prostate Cancer Cells via FOXM1 Transcription

OTUB1-mediated deubiquitination of FOXM1 up-regulates ECT-2 to promote tumor progression in renal cell carcinoma

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