Foxo3a Suppression of Urothelial Cancer Invasiveness through Twist1, Y-Box–Binding Protein 1, and E-Cadherin Regulation

Shiota, Masaki; Song, Yoo Hyun; Yokomizo, Akira; Kiyoshima, Keijiro; Tada, Yasuhiro; Uchino, Hiroshi; Uchiumi, Takeshi; Inokuchi, Junichi; Oda, Yoshinao; Kuroiwa, Kentaro; Tatsugami, Katsunori; Naito, Seiji

doi:10.1158/1078-0432.ccr-10-0376

Cited by 78 publications

(71 citation statements)

References 40 publications

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“…In fact, FOXO3a has been implicated in metastasis inhibition. For example, it has been shown that silencing FOXO3a in urothelial cells leads to increased cell motility, and that decreased FOXO3a expression is indicative of poor prognosis in patients with urothelial carcinomas (53). Similarly, ΔNp63α ablation in urothelial carcinoma cells results in increased cell motility (62).…”

Section: Discussionmentioning

confidence: 99%

“…In particular, Akt directly phosphorylates and inhibits nuclear translocation as well as transactivation activity of the FOXO family of proteins, including FOXO3a (also known as FKHRL1) and FOXO1 (also known as FKHR), which have been shown to play a role in regulating cell migration and invasion (53,54). We investigated whether FOXO transcription factors are involved in regulation of ΔNp63α expression.…”

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confidence: 99%

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ΔNp63α is a common inhibitory target in oncogenic PI3K/Ras/Her2-induced cell motility and tumor metastasis

Liang

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Activation of phosphatidylinositol 3 kinase (PI3K), Ras, and Her2 signaling plays a critical role in cancer development. Hotspot constitutive activating mutations in oncogenes, such as PIK3CA encoding the p110α catalytic subunit or RAS, as well as overexpression of Her2, are frequently found in human tumors and cancers. It has been well established that activation of these oncogenes profoundly promotes tumor metastasis, whereas decreased expression of ΔNp63α, the major protein isoform of the p53-related p63 expressed in epithelial cells, has been associated with cancer metastasis. In this study, we demonstrate that hotspot oncogenic mutations on PIK3CA and RAS, including p110α H1047R , K-Ras G12V , and H-Ras G12V , as well as activation of Her2, all led to suppression of ΔNp63α expression via Akt-fork-head transcription factor 3a (Akt-FOXO3a) signaling, resulting in increased cell motility and tumor metastasis. Expression of ΔNp63α effectively reversed p110α H1047R -, K-Ras G12V -, H-Ras G12V -, or Her2-induced cell motility in vitro and tumor metastasis in mouse models. We show that ΔNp63α was a direct FOXO3a transcriptional target and that expression of FOXO3a and ΔNp63α was correlated in human cancer biopsy samples. Together, these results demonstrate that ΔNp63α is a common inhibitory target of oncogenic PI3K, Ras, and Her2, and that ΔNp63α may function as a critical integrator of oncogenic signaling in cancer metastasis.PIK3CA | Ras | Her2 | ΔNp63α | cancer metastasis

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

ΔNp63α is a common inhibitory target in oncogenic PI3K/Ras/Her2-induced cell motility and tumor metastasis

Liang

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…The repression of p300 was associated with Twist1 up-regulation and E-cadherin reduction by Foxo3a-knockdown in KK47 cell line. These results suggest a putative correlation between p300 and Twist1 in the modulation of urothelial cancer invasiveness [11]. Epigenetic activation of Twist1 was confirmed by histone acetyltransferase CBP, which cooperated with metadherin to increase Twist1 expression in breast cancer [12].…”

Section: Acetylation Of Twistmentioning

confidence: 71%

Post-translational modifications of EMT transcriptional factors in cancer metastasis

2016

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Metastasis is an important reason for death of cancer patients which characterized as the formation of secondary cancers at distant sites. Epithelial– mesenchymal transition (EMT) is a dynamic process that appear to facilitate tumor metastasis in various cancers by switching epithelial cells into mesenchymal properties. Although previous investigation suggested a key role of EMT transcriptional factors in suppression of E-cadherin, the association of these factors with other cellular regulators in cancer metastasis need to be fully elucidated. Post-translational modifications (PTMs), such as acetylation and phosphorylation, have emerged as an important mechanism to modulate biological behavior of substrate proteins. In this review, we summarized protein modification and subsequent function changes of Snail, Twist and ZEB, as well as their influence on tumor progression. Acetylation of EMT transcriptional factors usually cause nuclear localization and/or protein stabilization thus contribute to E-cadherin repression. Besides, Twist and ZEB were phosphorylated by diverse kinases to promote metastasis in many cancers, while Snail was negatively regulated by phosphorylation to degradation. Then, the potential of therapy for metastasis by targeting PTMs-involved regulation of EMT transcriptional factors were discussed.

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“…FOXO3a negatively regulates Twist1 and Y-box-binding protein 1 (YB-1), and positively regulated E-cadherin in With FOXO3a PAX3 acts as a prognostic factor [94].…”

Section: Urothelial Cancermentioning

confidence: 99%

“…Similarly, PAX3 can modulate the expression of FOXO3, another type of transcription factor that belongs to the FOXO family that are involved in multiple signaling pathways and plays critical roles in a number of physiologic and pathologic processes [97]. Cancer patients with low FOXO3a expression had poor disease-free survival, cancer-specific survival, and overall survival [94].…”

Section: Foxo-pax3 Association In Tumor Suppressionmentioning

confidence: 99%

PAX3: A Molecule with Oncogenic or Tumor Suppressor Function Is Involved in Cancer

Arasu

Murugan

Essa

et al. 2018

BioMed Research International

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Metastasis is the most deadly aspect of cancer and results from acquired gene regulation abnormalities in tumor cells. Transcriptional regulation is an essential component of controlling of gene function and its failure could contribute to tumor progression and metastasis. During cancer progression, deregulation of oncogenic or tumor suppressive transcription factors, as well as master cell fate regulators, collectively influences multiple steps of the metastasis cascade, including local invasion and dissemination of the tumor to distant organs. Transcription factor PAX3/Pax3, which contributes to diverse cell lineages during embryonic development, plays a major role in tumorigenesis. Mutations in this gene can cause neurodevelopmental disease and the existing literature supports that there is a potential link between aberrant expression of PAX3 genes in adult tissues and a wide variety of cancers. PAX3 function is tissue-specific and could contribute to tumorigenesis either directly as oncogene or as a tumor suppressor by losing its function. In this review, we discuss comprehensively the differential role played by PAX3 in various tissues and how its aberrant expression is implicated in disease development. This review particularly highlights the oncogenic and tumor suppressor role played by PAX3 in different cancers and underlines the importance of precisely identifying tissue-specific role of PAX3 in order to determine its exact role in development of cancer.

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Foxo3a Suppression of Urothelial Cancer Invasiveness through Twist1, Y-Box–Binding Protein 1, and E-Cadherin Regulation

Cited by 78 publications

References 40 publications

ΔNp63α is a common inhibitory target in oncogenic PI3K/Ras/Her2-induced cell motility and tumor metastasis

ΔNp63α is a common inhibitory target in oncogenic PI3K/Ras/Her2-induced cell motility and tumor metastasis

Post-translational modifications of EMT transcriptional factors in cancer metastasis

PAX3: A Molecule with Oncogenic or Tumor Suppressor Function Is Involved in Cancer

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