Matricellular protein SPARC/osteonectin expression is regulated by DNA methylation in its core promoter region

Torres-Núñez, Eva; Cal, Laura; Suárez-Bregua, Paula; Gómez-Marín, Carlos; Morán, Paloma; Gómez-Skármeta, José Luis; Rotllant, Josep

doi:10.1002/dvdy.24267

Cited by 6 publications

(6 citation statements)

References 35 publications

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“…A rare expression of the SPARC protein in NSCLC cells was also observed in our learning cohort (only 1/21 cases); as a consequence, it was not possible to prove a statistically significant correlation between methylation of SPARC and its expression in tumor cells of lung tissues; moreover, SPARC protein expression data are not available on the TCGA datasets. Despite this, a good inverse correlation between SPARC methylation and its mRNA levels under 5-Aza-CdR treatment was observed in the A549 cell line, thus corroborating the idea of a regulatory role of some CpGs at the SPARC promoter region among those ones that Gao and colleagues have identified and called CpG region 1 (which contains CpG sites 1-7 and includes SP1 binding consensus sequence) and CpG region 2 groups (CpG sites 8-12, which includes AP2 binding consensus sequences) [18,32].…”

Section: Discussionsupporting

confidence: 66%

Potential Prognostic Role of SPARC Methylation in Non-Small-Cell Lung Cancer

Fabrizio

Sparaneo

Fontana

et al. 2020

Cells

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The silencing of SPARC (secreted protein acid and rich in cysteine) gene through methylation of its promoter region represents a common event in many solid tumors and it is frequently associated with tumor progression and an aggressive clinical outcome. Anyhow, the data concerning the epigenetic mechanism of SPARC deregulation and its prognostic value in lung cancer are still incomplete. We explored the aberrant methylation of SPARC and its effects in 4 non-small cell lung cancer (NSCLC) cell lines and 59 NSCLC tissues and correlated the methylation levels with clinical-pathological features and disease outcome of patients. In 3 out of 4 tumor cell lines high SPARC methylation levels were observed. An inverse correlation between the epigenetic silencing and SPARC expression was confirmed by 5-Aza-2′-deoxycytidine ((5-Aza-CdR) treatment that also significantly induced a reduction in cell viability, proliferation and tumor cell migration. In tissues, the DNA methylation levels of the SPARC gene were significantly lower in paired non-neoplastic lungs (NLs) and normal lungs distant from tumor (NLDTs) than in NSCLCs (p = 0.002 and p = 0.0034 respectively). A promoter hypermethylation was detected in 68% of squamous cell carcinoma (SqCCs, 17/25) and 56% of adenocarcinoma (ADCs, 19/34), with SqCC showing the highest levels of methylation. Higher SPARC methylation levels were significantly associated with higher mortality risk both in all NSCLCs early stage patients (Hazard Ratio, HR = 1.97; 95% Confidence Interval, CI: 1.32–2.93; p = 0.001) and in those with SqCC (HR = 2.96; 95% CI: 1.43–6.12; p = 0.003). Promoter methylation of SPARC gene should represent an interesting prognostic biomarker in NSCLC, with potential application in the squamous early-stage context. Further research in this setting on larger independent cohorts of lung patients with different histologies and stages of disease are warranted.

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Section: Discussionsupporting

confidence: 66%

Potential Prognostic Role of SPARC Methylation in Non-Small-Cell Lung Cancer

Fabrizio

Sparaneo

Fontana

et al. 2020

Cells

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“…Methylated genes, such as CDH11 , EphA5 , and HS3ST2 [32], could therefore be used as biomarkers for GC. In previous research, Torres-Núñez et al[33] found that SPARC expression was regulated by DNA methylation in its core promoter region.…”

Section: Discussionmentioning

confidence: 99%

Aberrant methylation of secreted protein acidic and rich in cysteine gene and its significance in gastric cancer

Shao

Zhou

Dai

2019

WJG

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BACKGROUNDAberrant methylation in DNA regulatory regions could downregulate tumor suppressor genes without changing the sequences. However, our knowledge of secreted protein acidic and rich in cysteine (SPARC) and its aberrant methylation in gastric cancer (GC) is still inadequate. In the present research, we performed fundamental research to clarify the precise function of methylation on SPARC and its significance in GC.AIMTo investigate promoter methylation and the effects of the SPARC gene in GC cells and tissues and to evaluate its clinical significance.METHODSPlasmids that overexpressed the SPARC gene were transfected into human GC BGC-823 cells; non-transfected cells were used as a control group (NC group). Quantitative real-time polymerase chain reaction and western blotting (WB) were then used to detect the expression of SPARC. Methylation-specific polymerase chain reaction was executed to analyze the gene promoter methylation status. Cell viability was measured by the cell counting kit-8 assay. The migration and invasion ability of cells were detected by scratch assays and transwell chamber assays, respectively. Cell cycle events and apoptosis were observed with a flow cytometer.RESULTSThe expression of SPARC mRNA in GC tissues and cells was significantly lower and showed differing degrees of hypermethylation, respectively, than that in normal adjacent tissues and control cells. Treatment with 5-Aza-2’-deoxycytidine (5-Aza-Cdr) was able to restore the expression of SPARC and reverse promoter hypermethylation. Overexpression of the SPARC gene significantly inhibited proliferation, migration, and invasion of GC cells, while also causing cell cycle arrest and apoptosis; the NC group exhibited the opposite effects.CONCLUSIONThis study demonstrated that SPARC could function as a tumor suppressor and might be silenced by promoter hypermethylation. Furthermore, in GC cells, SPARC inhibited migration, invasion, and proliferation, caused cell cycle arrest at the G0/G1 phase, and promoted apoptosis.

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“…DNA methylation was quantified using larval DNA digested by MCrBC enzyme as previously done [ 48 ] following the kit instructions.…”

Section: Methodsmentioning

confidence: 99%

Histone H4 acetylation regulates behavioral inter-individual variability in zebrafish

et al. 2018

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BackgroundAnimals can show very different behaviors even in isogenic populations, but the underlying mechanisms to generate this variability remain elusive. We use the zebrafish (Danio rerio) as a model to test the influence of histone modifications on behavior.ResultsWe find that laboratory and isogenic zebrafish larvae show consistent individual behaviors when swimming freely in identical wells or in reaction to stimuli. This behavioral inter-individual variability is reduced when we impair the histone deacetylation pathway. Individuals with high levels of histone H4 acetylation, and specifically H4K12, behave similarly to the average of the population, but those with low levels deviate from it. More precisely, we find a set of genomic regions whose histone H4 acetylation is reduced with the distance between the individual and the average population behavior. We find evidence that this modulation depends on a complex of Yin-yang 1 (YY1) and histone deacetylase 1 (HDAC1) that binds to and deacetylates these regions. These changes are not only maintained at the transcriptional level but also amplified, as most target regions are located near genes encoding transcription factors.ConclusionsWe suggest that stochasticity in the histone deacetylation pathway participates in the generation of genetic-independent behavioral inter-individual variability.Electronic supplementary materialThe online version of this article (10.1186/s13059-018-1428-y) contains supplementary material, which is available to authorized users.

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Matricellular protein SPARC/osteonectin expression is regulated by DNA methylation in its core promoter region

Cited by 6 publications

References 35 publications

Potential Prognostic Role of SPARC Methylation in Non-Small-Cell Lung Cancer

Potential Prognostic Role of SPARC Methylation in Non-Small-Cell Lung Cancer

Aberrant methylation of secreted protein acidic and rich in cysteine gene and its significance in gastric cancer

Histone H4 acetylation regulates behavioral inter-individual variability in zebrafish

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