FOXA1 antagonizes EZH2-mediated CDKN2A repression in carcinogenesis

Tong, Tanjun

doi:10.1016/j.bbrc.2014.09.092

Cited by 26 publications

(24 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For example, histone H3K27 methyltransferase EZH2 is upregulated in various types of cancer such as cancer of the breast, colon and prostate [15]. Moreover, EZH2 has received attention as a target for cancer treatment because EZH2-mediated tri-methylation of histone H3K27 results in inactivation of tumor suppressor genes such as PSP94 and p16 INK4a [16–18]. Overexpression of the YY1 has been reported in various cancers including that of breast and prostate [19, 20].…”

Section: Introductionmentioning

confidence: 99%

SFMBT2 (Scm-like with four mbt domains 2) negatively regulates cell migration and invasion in prostate cancer cells

et al. 2016

View full text Add to dashboard Cite

Metastatic prostate cancer is the leading cause of morbidity and mortality in men. In this study, we found that expression level of SFMBT2 is altered during prostate cancer progression and has been associated with the migration and invasion of prostate cancer cells. The expression level of SFMBT2 is high in poorly metastatic prostate cancer cells compared to highly metastatic prostate cancer cells. We also found that SFMBT2 knockdown elevates MMP-2, MMP-3, MMP-9, and MMP-26 expression, leading to increased cell migration and invasion in LNCaP and VCaP cells. SFMBT2 interacts with YY1, RNF2, N-CoR and HDAC1/3, as well as repressive histone marks such as H3K9me2, H4K20me2, and H2AK119Ub which are associated with transcriptional repression. In addition, SFMBT2 knockdown decreased KAI1 gene expression through up-regulation of N-CoR gene expression. Expression of SFMBT2 in prostate cancer was strongly associated with clinicopathological features. Patients having higher Gleason score (≥ 8) had substantially lower SFMBT2 expression than patients with lower Gleason score. Moreover, tail vein or intraprostatic injection of SFMBT2 knockdown LNCaP cells induced metastasis. Taken together, our findings suggest that regulation of SFMBT2 may provide a new therapeutic strategy to control prostate cancer metastasis as well as being a potential biomarker of metastatic prostate cancer.

show abstract

Section: Introductionmentioning

confidence: 99%

SFMBT2 (Scm-like with four mbt domains 2) negatively regulates cell migration and invasion in prostate cancer cells

et al. 2016

View full text Add to dashboard Cite

show abstract

“…The kinase activities of the CDK-cyclin complexes are negatively modulated by CDK inhibitors (CKIs) including p16 INK4a , p21 Waf1/Cip1 , and p27 Kip1 , all of which modulate both cell proliferation and cell death. Specifically, p16 INK4a is a well characterized inhibitor of d -type cyclin-dependent kinases [34] and its upregulation is one of the pivotal nodes of activated tumour suppressor network during senescence [35,36], arresting cells in early G1 phase. In this complex pathway, the proteasome system covers a crucial role in cell cycle progression because it controls the proteolytic degradation of cyclins and CKIs [37,38,39,40].…”

Section: Resultsmentioning

confidence: 99%

APEH Inhibition Affects Osteosarcoma Cell Viability via Downregulation of the Proteasome

Palumbo

Gogliettino

Cocca

et al. 2016

IJMS

View full text Add to dashboard Cite

The proteasome is a multienzymatic complex that controls the half-life of the majority of intracellular proteins, including those involved in apoptosis and cell-cycle progression. Recently, proteasome inhibition has been shown to be an effective anticancer strategy, although its downregulation is often accompanied by severe undesired side effects. We previously reported that the inhibition of acylpeptide hydrolase (APEH) by the peptide SsCEI 4 can significantly affect the proteasome activity in A375 melanoma or Caco-2 adenocarcinoma cell lines, thus shedding new light on therapeutic strategies based on downstream regulation of proteasome functions. In this work, we investigated the functional correlation between APEH and proteasome in a panel of cancer cell lines, and evaluated the cell proliferation upon SsCEI 4-treatments. Results revealed that SsCEI 4 triggered a proliferative arrest specifically in osteosarcoma U2OS cells via downregulation of the APEH–proteasome system, with the accumulation of the typical hallmarks of proteasome: NF-κB, p21Waf1, and polyubiquitinylated proteins. We found that the SsCEI 4 anti-proliferative effect involved a senescence-like growth arrest without noticeable cytotoxicity. These findings represent an important step toward understanding the mechanism(s) underlying the APEH-mediated downregulation of proteasome in order to design new molecules able to efficiently regulate the proteasome system for alternative therapeutic strategies.

show abstract

“…INK4a by FOXA1 counteracts its tumorigenic repression of by EZH2 in cancers (20). This indicated that FOXA1 may have a role in EC that is not linked to ERα, and that the function of FOXA1 could be organ specific.…”

Section: Discussionmentioning

confidence: 97%

“…INK4a promoter, which is the key senescence-associated gene (10,20). To understand the interplay of chromatin, senescence and EC, further studies are required to elucidate the functional and causal roles of senescence-associated chromatin features in preventing tumor phenotype and to delineate the underlying mechanisms.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Forkhead-box A1 induces cell senescence in endometrial cancer by regulating p16INK4a

et al. 2016

View full text Add to dashboard Cite

Abstract. We previously identified FOXA1 as a tumorsuppressor in EC cells. In the present study, we sought to delineate the different roles of FOXA1 associated with cell senescence and further investigated the correlation between FOXA1 and p16INK4a in the progression of EC. Using reverse transcription-quantitative PCR (RT-qPCR), we found that FOXA1 expression was significantly downregulated in EC cells compared to that in normal endometrial cells. Functionally, senescence-associated β-galactosidase staining, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), clonogenic and Transwell assays showed that in addition to acting as a pioneer factor, FOXA1 was significantly upregulated in senescent EC cells. Furthermore, restoration of FOXA1 expression triggered multiple steps of cellular senescence in EC cells and activated p16INK4a expression. All of these findings indicate that FOXA1 promotes cell senescence in EC by interaction with p16INK4a , possibly via the AKT pathway. Notably, a selective PI3K inhibitor raised the possibility that FOXA1-induced senescence is associated with the AKT pathway in EC cells. Collectively, the present study provides a conceivable molecular mechanism by which cell senescence acts as the barrier to EC, and is regulated by FOXA1-induced p16INK4a expression. This may be a newly identified regulatory mechanism of cell senescence in EC.

show abstract

FOXA1 antagonizes EZH2-mediated CDKN2A repression in carcinogenesis

Cited by 26 publications

References 27 publications

SFMBT2 (Scm-like with four mbt domains 2) negatively regulates cell migration and invasion in prostate cancer cells

SFMBT2 (Scm-like with four mbt domains 2) negatively regulates cell migration and invasion in prostate cancer cells

APEH Inhibition Affects Osteosarcoma Cell Viability via Downregulation of the Proteasome

Forkhead-box A1 induces cell senescence in endometrial cancer by regulating p16INK4a

Contact Info

Product

Resources

About