FOXM1 and Cancer: Faulty Cellular Signaling Derails Homeostasis

Kalathil, Dhanya; John, Samu; Nair, Asha S.

doi:10.3389/fonc.2020.626836

Cited by 102 publications

(81 citation statements)

References 245 publications

(175 reference statements)

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“…Among the different classes of ncRNAs, microRNAs (miRNA) bind to and destabilize messenger RNAs (mRNA), while long non-coding RNAs (lncRNA) and circular RNAs (circRNA) can contain miRNA-complementary sites that competitively bind to miRNAs and reduce the number of available miRNAs that can bind to mRNA targets; this is an action known as miRNA sponging [ 180 , 181 ]. Thus, ncRNAs play a major role in FOXM1 regulation, with over 40 implicated to date [ 182 ].…”

Section: Foxm1 Is Overexpressed and Activated In Ovarian Cancermentioning

confidence: 99%

FOXM1: A Multifunctional Oncoprotein and Emerging Therapeutic Target in Ovarian Cancer

Liu

Barger

Karpf

2021

Cancers

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Forkhead box M1 (FOXM1) is a member of the conserved forkhead box (FOX) transcription factor family. Over the last two decades, FOXM1 has emerged as a multifunctional oncoprotein and a robust biomarker of poor prognosis in many human malignancies. In this review article, we address the current knowledge regarding the mechanisms of regulation and oncogenic functions of FOXM1, particularly in the context of ovarian cancer. FOXM1 and its associated oncogenic transcriptional signature are enriched in >85% of ovarian cancer cases and FOXM1 expression and activity can be enhanced by a plethora of genomic, transcriptional, post-transcriptional, and post-translational mechanisms. As a master transcriptional regulator, FOXM1 promotes critical oncogenic phenotypes in ovarian cancer, including: (1) cell proliferation, (2) invasion and metastasis, (3) chemotherapy resistance, (4) cancer stem cell (CSC) properties, (5) genomic instability, and (6) altered cellular metabolism. We additionally discuss the evidence for FOXM1 as a cancer biomarker, describe the rationale for FOXM1 as a cancer therapeutic target, and provide an overview of therapeutic strategies used to target FOXM1 for cancer treatment.

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Section: Foxm1 Is Overexpressed and Activated In Ovarian Cancermentioning

confidence: 99%

FOXM1: A Multifunctional Oncoprotein and Emerging Therapeutic Target in Ovarian Cancer

Liu

Barger

Karpf

2021

Cancers

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“…DCLK1 expression was significantly promoted by Olaparib. DCLK1 is a microtubule-associated oncoprotein that regulates cell apoptosis and DNA repair to promote tumorigenesis [ 36 ]. Therefore, the overexpression of DCLK1 contributes to the generation of adaptive resistance.…”

Section: Discussionmentioning

confidence: 99%

FDI-6 inhibits the expression and function of FOXM1 to sensitize BRCA-proficient triple-negative breast cancer cells to Olaparib by regulating cell cycle progression and DNA damage repair

Wang

Huang

et al. 2021

Cell Death Dis

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Inducing homologous-recombination (HR) deficiency is an effective strategy to broaden the indications of PARP inhibitors in the treatment of triple-negative breast cancer (TNBC). Herein, we find that repression of the oncogenic transcription factor FOXM1 using FOXM1 shRNA or FOXM1 inhibitor FDI-6 can sensitize BRCA-proficient TNBC to PARP inhibitor Olaparib in vitro and in vivo. Mechanistic studies show that Olaparib causes adaptive resistance by arresting the cell cycle at S and G2/M phases for HR repair, increasing the expression of CDK6, CCND1, CDK1, CCNA1, CCNB1, and CDC25B to promote cell cycle progression, and inducing the overexpression of FOXM1, PARP1/2, BRCA1/2, and Rad51 to activate precise repair of damaged DNA. FDI-6 inhibits the expression of FOXM1, PARP1/2, and genes involved in cell cycle control and DNA damage repair to sensitize TNBC cells to Olaparib by blocking cell cycle progression and DNA damage repair. Simultaneously targeting FOXM1 and PARP1/2 is an innovative therapy for more patients with TNBC.

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“…Identifying TF with malignant characteristics can provide a comprehensive view for explaining tumor biology. Forkhead / wing helix domain transcription factor FoxM1, as an oncoprotein, affected the occurrence and development of cancer through trans activation of related oncogenes 22,23 . Its expression had been proved to be increased in various cancers 22,24 .…”

Section: Discussionmentioning

confidence: 99%

Berberine Inhibits FoxM1 Dependent Transcriptional Regulation of POLE2 and Interferes with the Survival of Lung Adenocarcinoma

Sun

Fan

et al. 2021

Preprint

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Background：Berberine is one of the most interesting and promising natural anticancer drugs. POLE2 is involved in many cellular functions such as DNA replication and is highly expressed in a variety of cancers. However, the specific molecular mechanism of berberine interfering with POLE2 expression in lung adenocarcinoma (LUAD) is still unknown to a great extent.Method:The KEGG database (Release 91.0) and Gene Ontology (GO) category database were used for functional annotation of differentially expressed genes after berberine treatment. Reproducibility assessment using TCGA dataset. The biological functions of berberine in LUAD were investigated by a series of in vitro and in vivo experiments: MTT, colony formation, mouse xenograft and plasmid transfection. The molecular mechanisms of berberine were demonstrated by plasmid transfection, quantitative RT-PCR and Western blotting.Result:The elevated expression of FoxM1 and the high enrichment of DNA replication pathway were confirmed in LUAD by microarray and TCGA analysis, and were positively correlated with poor prognosis. Functionally, berberine inhibited the proliferation and survival of LUAD cell lines in vitro and in vivo. Mechanistically, berberine treatment down regulated the expression of FoxM1which closely related to survival, survival related genes in cell cycle and DNA replication pathway, and significantly down regulated the expression of survival related POLE2. Interestingly, we found that the transcription factor FoxM1 could act as a bridge between berberine and POLE2.Conclusion: Berberine significantly inhibited LUAD progression via the FoxM1/POLE2, and FoxM1/POLE2 may act as a clinical prognostic factor and a therapeutic target for LUAD. Berberine may be used as a promising therapeutic candidate for LUAD patients.

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FOXM1 and Cancer: Faulty Cellular Signaling Derails Homeostasis

Cited by 102 publications

References 245 publications

FOXM1: A Multifunctional Oncoprotein and Emerging Therapeutic Target in Ovarian Cancer

FOXM1: A Multifunctional Oncoprotein and Emerging Therapeutic Target in Ovarian Cancer

FDI-6 inhibits the expression and function of FOXM1 to sensitize BRCA-proficient triple-negative breast cancer cells to Olaparib by regulating cell cycle progression and DNA damage repair

Berberine Inhibits FoxM1 Dependent Transcriptional Regulation of POLE2 and Interferes with the Survival of Lung Adenocarcinoma

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