The Critical Role of Dysregulated FOXM1–PLAUR Signaling in Human Colon Cancer Progression and Metastasis

Li, Dawei; Wei, Ping; Peng, Zhihai; Huang, Chen; Tang, Huamei; Jia, Zhiliang; Cui, Jiujie; Xin, Le; Huang, Suyun; Xie, Keping

doi:10.1158/1078-0432.ccr-12-1588

Cited by 102 publications

(82 citation statements)

References 55 publications

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“…Recent studies demonstrated that FOXM1 plays an important role in regulating EMT (17,18,38,39) and Warburg effect (40). Our data here demonstrated that the Gas1 promoter was sufficient to allow FOXM1-dependent inactivation of gene expression in transactivation assays and led to the identification of a bona fide FOXM1 responsive element within a 424 bp fragment of the Gas1 promoter, which contained a DNA sequence to which FOXM1 can directly bind.…”

Section: Discussionsupporting

confidence: 58%

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Gas1 Inhibits Metastatic and Metabolic Phenotypes in Colorectal Carcinoma

Qin

Wei

et al. 2016

Molecular Cancer Research

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Growth arrest-specific 1 (Gas1) plays a critical role in growth suppression. Previous study indicated that Gas1 was closely associated with survival in patients with colorectal cancer; however, the underlying molecular mechanism remains unclear. In this study, we sought to determine the role of Gas1 in tumorigenesis and metastasis, and elucidate the possible mechanism. First, Gas1 was determined as a negative regulator of oncogenesis and metastasis in colorectal cancer. Mechanistically, Gas1 negatively regulated the aerobic glycolysis, a process that contributed to tumor progression and metastasis by providing energy source and building blocks for macromolecule synthesis. To further consolidate the role of Gas1 in glycolysis, the impact of Gas1 in the transcription of key glycolytic enzymes for glucose utilization was examined. As expected, GLUT4, HK2, and LDHB exhibited a decreased expression pattern. Consistent with this observation, an in vivo subcutaneous xenograft mouse model also confirmed the hypothesis that Gas1 is a negative regulator of glycolysis as reflected by the decreased 18FDG uptake in PET/CT system. Moreover, Gas1 negatively regulated the AMPK/mTOR/p70S6K signaling axis, a well-established cascade that regulates malignant cancer cell behaviors including proliferation, metastasis, and aberrant cancer metabolism. In the end, it was determined that Gas1 is a transcriptional target of FOXM1, whose role in colorectal cancer has been widely studied. Taken together, these studies establish Gas1 as a negative regulator in colorectal cancer.Implications: Gas1 suppresses cell proliferation, invasion, and aerobic glycolysis of colorectal cancer both in vitro and in vivo. Mechanistically, Gas1 inhibited EMT and the Warburg effect via AMPK/mTOR/p70S6K signaling, and Gas1 itself was directly regulated by the transcription factor FOXM1.

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Section: Discussionsupporting

confidence: 58%

“…6A). FOXM1 was selected for further investigation due to its well-established role in colorectal cancer (17,18). To validate the hypothesis, we first tested the impact of FOXM1 on Gas1 transcription in colon cancer cells and indicated FOXM1 as a negative regulator of Gas1 expression ( Fig.…”

Section: Gas1 Is Directly Regulated By the Transcription Factor Foxm1mentioning

confidence: 99%

Gas1 Inhibits Metastatic and Metabolic Phenotypes in Colorectal Carcinoma

Qin

Wei

et al. 2016

Molecular Cancer Research

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“…Further, overexpression of PLAU largely rescued self-renewal, migration, invasion and vascular formation defects induced by HMGA2 knockdown. Interestingly, FOXM1 transactives PLAUR expression to promote colon cancer progression and metastasis [51]. These suggest the presence of the HMGA2-FOXM1/PLAU-PLAUR axis in maintaining GIC self-renewal and aggressiveness.…”

Section: Discussionmentioning

confidence: 99%

HMGA2 sustains self-renewal and invasiveness of glioma-initiating cells

Zhong

Luo

et al. 2016

Oncotarget

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Glioblastoma multiforme (GBM) is the most common type of brain tumors with dismal outcomes. The mesenchymal phenotype is the hallmark of tumor aggressiveness in GBMs. Perivascular smooth muscle cells (pericytes) are essential in homeostasis of normal and glioma tissues. Here we found HMGA2, an architectural transcription factor that promotes mesenchymal phenotypes in a number of solid tumors, is highly expressed in mesenchymal subtype of GBMs and labels both glioma pericytes and glioma-initiating cells (GICs). Accordingly, depletion of HMGA2 in GICs resulted in compromised self-renewal and tumorigenic capability, as well as undermined mesenchymal or pericyte differentiation. We further showed HMGA2 allows expressions of FOXM1 and PLAU to maintain GIC propagation, gliomagenesis and aggressiveness both in vitro and in vivo. Therefore, suppressing HMGA2-mediated GIC self-renewal and invasiveness might be a promising means to treat GBMs.

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“…FOXM1 dysregulation leads to uncontrolled cell growth and epithelial-mesenchymal transition [7, 8] in somatic malignancies including breast [9], liver [10], lung [11], and ovarian carcinomas [12]. Although FOXM1 is a predicted target of the ubiquitin-proteosome system [13–15], little is known about either its degradation-related domains or its affinity for different polyUb chains.…”

Section: Introductionmentioning

confidence: 99%

OTUB1-catalyzed deubiquitination of FOXM1 facilitates tumor progression and predicts a poor prognosis in ovarian cancer

Wang

Zhou

et al. 2016

Oncotarget

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Ubiquitination is essential for regulation of cell physiology, protein stability, and signal transduction [1]. Its dysregulation is an important factor in many diseases, including cancer. We explored the potential OTUB1-catalyzed deubiquitination of FOXM1, a transcription factor linked to carcinogenesis, and the biological consequence of that interaction in ovarian cancer. We found that FOXM1 is ubiquitinated by multiple polyUb chains and targeted for proteosomal degradation in a reaction dependent on its ubiquitination-required KEN box. Additionally, the OTUB1 N-terminus and catalytic triad bind to FOXM1, specifically catalyzing cleavage of the K48-specific ubiquitin linkage from FOXM1. Moreover, OTUB1-FOXM1 interaction drives tumor progression and OTUB1 expression predicts a poor prognosis in ovarian cancer. Our study suggests that inhibiting OTUB1-FOXM1 interaction is a potential new avenue for ovarian cancer therapy.

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The Critical Role of Dysregulated FOXM1–PLAUR Signaling in Human Colon Cancer Progression and Metastasis

Cited by 102 publications

References 55 publications

Gas1 Inhibits Metastatic and Metabolic Phenotypes in Colorectal Carcinoma

Gas1 Inhibits Metastatic and Metabolic Phenotypes in Colorectal Carcinoma

HMGA2 sustains self-renewal and invasiveness of glioma-initiating cells

OTUB1-catalyzed deubiquitination of FOXM1 facilitates tumor progression and predicts a poor prognosis in ovarian cancer

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