FOXM1 and STAT3 interaction confers radioresistance in glioblastoma cells

Maachani, Uday B.; Shankavaram, Uma; Kramp, Tamalee; Tofilon, Philip J.; Camphausen, Kevin; Tandle, Anita

doi:10.18632/oncotarget.12670

Cited by 62 publications

(48 citation statements)

References 45 publications

(57 reference statements)

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“…Increase of FOXM1 expression was linked to the direct interaction of FOXM1 with STAT3 (17). Co-localization of FOXM1 and STAT3 in the nucleus of radiation-treated cells was also confirmed by immunofluorescence (17) and suppression of STAT3 repressed FOXM1 expression. In addition, FOXM1 inhibition sensitized glioblastoma cells to radiation.…”

Section: Stat3 Interacts With Foxm1 In Glioblastoma After Radiatiomentioning

confidence: 99%

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FOXM1 in Cancer: Interactions and Vulnerabilities

2017

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FOXM1 is a transcription factor of the Forkhead family that is required for cell proliferation of normal cells. However, FOXM1 is repeatedly overexpressed in a variety of human cancers and it has been implicated in all major hallmarks of cancer delineated by Hanahan and Weinberg. It has been postulated that the oncogenic potential of FOXM1 is determined by its capacity to trans-activate target genes that are implicated in different phases of cancer development. However, FOXM1 may also play an oncogenic role by interacting with other proteins such as beta-catenin or SMAD3 to induce oncogeneic WNT and TGF-β signaling pathways, respectively. In this review, I will discuss the protein-protein interactions of FOXM1 that are critical for cancer development and may represent novel targets for anticancer drugs.

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Section: Stat3 Interacts With Foxm1 In Glioblastoma After Radiatiomentioning

confidence: 99%

“…In addition, FOXM1 inhibition sensitized glioblastoma cells to radiation. The authors suggested that the FOXM1/STAT3 interaction may contribute to the activation of FOXM1 expression and resistance to radiation in glioma stem cells (17). …”

Section: Stat3 Interacts With Foxm1 In Glioblastoma After Radiatiomentioning

confidence: 99%

FOXM1 in Cancer: Interactions and Vulnerabilities

2017

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“…FOXM1 is reported to promote HR (Khongkow et al, 2014;Maachani et al, 2016;Monteiro et al, 2013;Park et al, 2012); however, FOXM1 depletion in OVCAR8 cells did not appear to alter the expression of DNA damage response genes, including BRCA2 ( Figure S13).…”

Section: Foxm1 and Rhno1 Cooperatively Promote Hrmentioning

confidence: 99%

“…The most common oncogenic function assigned to FOXM1 is deregulation of the G2/M checkpoint to promote cellular proliferation (Costa, 2005;Laoukili et al, 2005;Wonsey and Follettie, 2005). FOXM1 also promotes HR (Khongkow et al, 2014;Maachani et al, 2016;Monteiro et al, 2013;Park et al, 2012) and chemoresistance (Carr et al, 2010;Fang et al, 2018;Kwok et al, 2010;Tassi et al, 2017;Zhao et al, 2014). Pan-cancer analyses have demonstrated increased FOXM1 expression across a variety of cancers and a robust connection to genomic instability and poor prognosis (Barger et al, 2019;Carter et al, 2006;Gentles et al, 2015;Jiang et al, 2015;Li et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Co-regulation and functional cooperativity of FOXM1 and RHNO1 bidirectional genes in ovarian cancer

Barger

Branick

Chee

et al. 2019

Preprint

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We report that the oncogenic transcription factor FOXM1 is arranged in a head-to-head configuration with RHNO1, a gene involved in the ATR/CHK1-dependent DNA replication stress (DRS) response. FOXM1 and RHNO1 are both amplified and upregulated in high-grade serous ovarian cancer (HGSC). FOXM1 and RHNO1 expression are closely associated in normal and cancer tissues, including single cells, and a bidirectional promoter (F/R-BDP) mediates balanced expression. Targeting of FOXM1 and RHNO1 in HGSC cells using shRNA, CRISPR mutagenesis, or CRISPR interference directed to the F/R-BDP reduced DNA homologous recombination repair (HR) capacity, increased DNA damage, reduced clonogenic survival, and sensitized HGSC cells to the poly-ADP ribosylase inhibitor (PARPi) olaparib. Thus, there is functional cooperativity between FOXM1 and RHNO1 in cancer cells, and combinatorial targeting of this bidirectional gene pair may be a novel cancer therapeutic strategy. More broadly, our data provide evidence that bidirectional gene units function in human cancer.Here, we show that FOXM1 and RHNO1 are co-amplified and co-expressed in HGSC, and that their expression in controlled by a bidirectional promoter (named the F/R-BDP). We additionally show that FOXM1 and RHNO1 they cooperatively promote HR, cell survival, and PARPi resistance. Co-regulation and functional cooperativity between FOXM1 and RHNO1 suggests that this bidirectional gene unit is a potential therapeutic target in HGSC and/or other cancers. More generally, our data provide evidence that cooperative bidirectional gene units functionally contribute to cancer. ResultsThe 12p13.33 amplicon contains FOXM1 and RHNO1, co-expressed bidirectional genes FOXM1 is located at 12p13.33, a region with frequent copy number gains in HGSC and several other cancers (Barger et al., 2019;Barger et al., 2015). 12p13.33 amplification was associated with reduced overall survival in HGSC but, unexpectedly, FOXM1 mRNA expression did not (Barger et al., 2015). The 12p13.33 amplicon includes 33 genes (Figure S1). To identify genes at 12p13.33 that might functionally cooperate with FOXM1, we performed expression correlation analyses. FOXM1 expression showed the strongest correlation with RHNO1 expression in HGSC (Figure 1A), pan-cancer (data not shown), and normal human tissues ( Figure S2). In addition, RHNO1 mRNA expression correlated with reduced HGSC survival (data not shown). Genomic analyses of FOXM1 and RHNO1 revealed a head-to-head arrangement with an intervening putative bidirectional promoter (BDP) ( Figure S3). Approximately 10% of human genes are arranged in this manner, and the gene pairs are frequently co-regulated and can function in similar biochemical pathways (Trinklein et al., 2004;Wakano et al., 2012;. The FOXM1/RHNO1 BDP (F/R-BDP) region contains a CpG island (CGI), a common feature of BDPs ( Figure S3) (Antequera, 2003;Takai and Jones, 2004;Wakano et al., 2012).BDPs are often enriched with specific histone modifications H3K4me3, H3K9ac, H3K27ac, and H3K4me2 (Bornelov et al., 20...

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“…Despite recent advances, glioma treatments are not curative, no matter the combinations of surgery, chemotherapy and/or radiotherapy used [2, 3]. Thus, it is necessary to further explore the mechanisms of glioma development to find new therapeutic targets for this disease.…”

Section: Introductionmentioning

confidence: 99%

CBX7 negatively regulates migration and invasion in glioma via Wnt/β-catenin pathway inactivation

Bao

Liu

et al. 2017

Oncotarget

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CBX7, a member of the Polycomb-group proteins, plays a significant role in normal and cancerous tissues and has been defined as a tumor suppressor in thyroid, breast and pancreatic cancers. However, its function in glioma remains undefined. CBX7 expression is decreased in glioma, especially in higher grade cases, according to data in the CGGA, GSE16001 and TCGA databases. Further experimental evidence has shown that exogenous CBX7 overexpression induced apoptosis and inhibited cell proliferation, colony formation and migration of glioma cells. In this study, we show that the invasive ability of glioma cells was decreased following CBX7 overexpression and CBX7 overexpression was associated with Wnt/β-catenin pathway inhibition, which also decreased downstream expression of ZEB1, a core epithelial-to-mesenchymal transition factor. This reduction in Wnt signaling is controlled by DKK1, a specific Wnt/β-catenin inhibitor. CBX7 enhances DKK1 expression by binding the DKK1 promoter, as shown in Luciferase reporter assays. Our data confirm that CBX7 inhibits EMT and invasion in glioma, which is manifested by influencing the expression of MMP2, MMP9, E-cadherin, N-cadherin and Vimentin in LN229, T98G cells and primary glioma cells (PGC). Furthermore, as a tumor suppressor, CBX7 expression is pivotal to reduce tumor invasion and evaluate prognosis.

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FOXM1 and STAT3 interaction confers radioresistance in glioblastoma cells

Cited by 62 publications

References 45 publications

FOXM1 in Cancer: Interactions and Vulnerabilities

FOXM1 in Cancer: Interactions and Vulnerabilities

Co-regulation and functional cooperativity of FOXM1 and RHNO1 bidirectional genes in ovarian cancer

CBX7 negatively regulates migration and invasion in glioma via Wnt/β-catenin pathway inactivation

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