WASF3 regulates miR-200 inactivation by ZEB1 through suppression of KISS1 leading to increased invasiveness in breast cancer cells

Teng, Yong; Mei, Yun; Hawthorn, Lesleyann; Cowell, John K.

doi:10.1038/onc.2012.565

Cited by 74 publications

(107 citation statements)

References 45 publications

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“…WASF3-mediated invasion is associated with downregulation of KISS1 (10,11) but this effect was not seen in WASF1- or WASF2-depleted cells (10). Knockdown of WASF3 also leads to downregulation of MMP9 expression and secretion (10).…”

Section: Resultsmentioning

confidence: 96%

“…Knockdown of WASF3 in breast and prostate cancer cells leads to a reduction in cell invasion in vitro and metastasis in xenograft models in vivo (5, 9). Non-metastatic cells do not express WASF3 (10), but reexpression in these cells leads to acquisition of the invasion phenotype. Although primarily considered a protein that regulates actin cytoskeleton dynamics, WASF3 has also been shown to have a regulatory function that affects expression of genes involved in metastasis such as KISS1, ZEB1 and miRNA-200s (10–12) and its activity and expression is regulated by proteins such as JAK2, HSP70, ABL and HIF1 (13–16), which have also been implicated in metastasis.…”

Section: Introductionmentioning

confidence: 99%

“…Non-metastatic cells do not express WASF3 (10), but reexpression in these cells leads to acquisition of the invasion phenotype. Although primarily considered a protein that regulates actin cytoskeleton dynamics, WASF3 has also been shown to have a regulatory function that affects expression of genes involved in metastasis such as KISS1, ZEB1 and miRNA-200s (10–12) and its activity and expression is regulated by proteins such as JAK2, HSP70, ABL and HIF1 (13–16), which have also been implicated in metastasis. WASF3 also interacts with the ATAD3A mitochondrial protein, which regulates its stability at the mitochondrial membrane (17).…”

Section: Introductionmentioning

confidence: 99%

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Targeting the WASF3–CYFIP1 Complex Using Stapled Peptides Suppresses Cancer Cell Invasion

et al. 2016

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Activation of the WASF3 protein by extracellular stimuli promotes actin cytoskeleton reorganization and facilitates cancer cell invasion, whereas WASF3 depletion suppresses invasion and metastasis. In quiescent cells, the interaction between WASF3 and a complex of proteins including CYFIP1 acts as a conformational restraint to prevent WASF3 activation. Therefore, we took advantage of this endogenous regulatory mechanism to investigate potential sites that disrupt WASF3 function. Here, we show that genetic knockdown of CYFIP1 in cancer cells led to the destabilization of the WASF3 complex, loss of WASF3 function, and suppressed invasion. Based on existing crystallographic data, we developed stapled peptides, referred to as WASF Helix Mimics (WAHM), that target an α-helical interface between WASF3 and CYFIP1. Treatment of highly invasive breast and prostate cancer cells with WAHM inhibitor peptides significantly reduced motility and invasion in vitro. Mechanistic investigations revealed that these inhibitors suppressed the interaction between Rac and the WASF3 complex, which has been shown to promote cell migration. Furthermore, peptide-mediated inhibition of WASF3 also resulted in the dysregulation of known downstream targets such as MMP-9 and KISS1. Finally, we demonstrate that this invasive phenotype is specific to WASF3 as depletion of WASF1 and WASF2, which can also bind to CYFIP1, did not affect invasion. Collectively, our findings suggest that targeting WASF3 function with WAHM peptides could represent a promising therapeutic strategy for preventing tumor invasion and metastasis.

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Section: Resultsmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Targeting the WASF3–CYFIP1 Complex Using Stapled Peptides Suppresses Cancer Cell Invasion

et al. 2016

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“…miR-200 family members are major regulators of epithelialmesenchymal transition (49) and are believed to be generally involved in cancer progression, metastasis, and chemoresistance (50). Downregulation of miR-200 family members was proposed to be essential for progression and invasiveness of breast (51,52) and ovarian cancer, and its high expression is associated with improved survival of ovarian (53) and pancreatic cancer patients (54). In female reproductive cancers, miR-200c was reported to be a marker of aggressiveness and chemoresistance (55).…”

Section: Discussionmentioning

confidence: 99%

Regulation of Complement-Dependent Cytotoxicity by MicroRNAs miR-200b, miR-200c, and miR-217

Hillman

Mazkereth

Farberov

et al. 2016

The Journal of Immunology

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The impact of microRNAs (miRNAs) known to regulate numerous biologic processes on complement-dependent cytotoxicity (CDC) was investigated in K562 cells. The C5b-9 complex is the executioner of CDC. Cells protect themselves from CDC by C5b-9 elimination, a process involving the mitochondrial chaperone mortalin/GRP75. Potential miR-200 (b and c) and miR-217 regulatory sites were identified in mortalin mRNA. Overexpression of miR-200b/c or miR-217 lowered the expression of mortalin mRNA. miRNA inhibitors for miR-200b, miR-200c, or miR-217 enhanced mortalin mRNA level. Unexpectedly, these miRNA modulators had no significant effect on mortalin protein level. Metabolic labeling analysis demonstrated that, to compensate for reduction in mortalin mRNA level, the cells increased the rate of synthesis of mortalin protein. Cells overexpressing miR-200b/c or miR-217 showed reduced sensitivity to CDC, whereas inhibition of miR-200c and miR-217 enhanced cell death. miR-200b/c overexpression reduced C5b-9 binding and enhanced its release from the cells and promoted mortalin relocation to the plasma membrane. Inhibition of miR-200 (b and c) and miR-217 had no effect on the expression level of the membrane complement-regulatory proteins CD46, CD55, and CD59. However, overexpression of miR-200b/c or miR-217 enhanced expression of CD46 and CD55 (not of CD59). Overall, the data demonstrate miRNA regulation of cell sensitivity to CDC. We identified miR-200b, miR-200c, and miR-217 as regulators of mortalin and, perhaps indirectly, of CD46 and CD55. Cell exposure to a sublytic dose of complement was shown to increase expression of miR-200 (b and c), suggesting that complement C5b-9 exerts a feedback-regulatory effect on these miRNAs.

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“…Additionally, miR-1 and miR-133 are both parasitic in the MIB1 gene, which regulates apoptosis [49]. Furthermore, NF-κB can regulate the expression of miR-200b, miR-30c and miR-152 [50][51][52], whereas miR-182, miR-183, miR-96 and miR-1 can be regulated by FOXO3 [53,54]. When combining the effect of these two inflammatory factors, two pathways associated with NAFLD were proposed (Fig.…”

Section: Cellular Physiology and Biochemistrymentioning

confidence: 99%

Aberrant Hepatic MicroRNA Expression in Nonalcoholic Fatty Liver Disease

Feng

Xu²,

Chen³

et al. 2014

Cell Physiol Biochem

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Background/Aim: Emerging evidence suggests that microRNA (miRNA) mediated gene regulation influences the maintenance of metabolic homeostasis, particularly the states of obesity and insulin resistance, thereby providing a potential link between miRNAs and nonalcoholic fatty liver disease (NAFLD). Methods: Sprague-Dawley rats fed a high-fat diet (HFD) were used to establish a rat model of NAFLD. The miRNA expression profile of liver tissues was evaluated using Illumina HiSeq deep sequencing. Selected miRNAs were then validated by real-time PCR at both 4-and 12-week time points. Furthermore, the expression levels of these miRNAs were assessed in HepG2 cells and human hepatocytes treated with free fatty acids (FFAs) and proinflammatory factors (tumour necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6). Results: Our results showed that consumption of a HFD for 4 weeks caused simple steatosis, which progressed to steatohepatitis at 12 weeks. miRNA deep sequencing analysis identified 44 known up-regulated miRNAs (fold change >1.5) and 12 down-regulated miRNAs (fold change <0.5). Among the abnormally expressed miRNAs, miR200a, miR-200b, miR-200c, miR-146a, miR-146b and miR-152 were up-regulated both in vitro and vivo. Interestingly, the expression levels of these six miRNAs were increased in HepG2 cells and human hepatocytes after treatment with FFAs and proinflammatory factors. Conclusion: These findings suggest a critical role for miRNAs in the pathogenesis of NAFLD.Y. Y. Feng and X. Q. Xu authors contributed equally to this work.

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WASF3 regulates miR-200 inactivation by ZEB1 through suppression of KISS1 leading to increased invasiveness in breast cancer cells

Cited by 74 publications

References 45 publications

Targeting the WASF3–CYFIP1 Complex Using Stapled Peptides Suppresses Cancer Cell Invasion

Targeting the WASF3–CYFIP1 Complex Using Stapled Peptides Suppresses Cancer Cell Invasion

Regulation of Complement-Dependent Cytotoxicity by MicroRNAs miR-200b, miR-200c, and miR-217

Aberrant Hepatic MicroRNA Expression in Nonalcoholic Fatty Liver Disease

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