Methylation of
            <i>SLFN11</i>
            is a Marker of Poor Prognosis and Cisplatin Resistance in Colorectal Cancer

He, Tao; Zhang, Meiying; Zheng, Rong; Zheng, Shufang; Linghu, Enqiang; Herman, James G.; Guo, Mingzhou

doi:10.2217/epi-2017-0019

Cited by 48 publications

(35 citation statements)

References 24 publications

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“…Consistent with earlier analyses of the NCI-60 cell lines [19,20] and with growing evidence for the role of epigenetic mechanisms in SLFN11 inactivation [21,69,81], we found that increased methylation of the SLFN11 promoter was negatively correlated with SLFN11 expression and increased resistance of SCLC lines to DNA-damaging agents (Supplementary Figure 3). Association of SCLC promoter methylation with gene expression and with drug sensitivity are in agreement with the findings of He et al [82], who showed that increased methylation of the SLFN11 promoter in colorectal cancer cell lines and primary tumors led to downregulation of SLFN11 expression, increased tumor resistance to cisplatin, and decreased the 5-year overall patient survival and 5-year progression-free survival.…”

Section: Discussionsupporting

confidence: 91%

Epigenome-wide DNA methylation analysis of small cell lung cancer cell lines suggests potential chemotherapy targets

et al. 2020

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Background: Small cell lung cancer (SCLC) is an aggressive neuroendocrine lung cancer. SCLC progression and treatment resistance involve epigenetic processes. However, links between SCLC DNA methylation and drug response remain unclear. We performed an epigenome-wide study of 66 human SCLC cell lines using the Illumina Infinium MethylationEPIC BeadChip array. Correlations of SCLC DNA methylation and gene expression with in vitro response to 526 antitumor agents were examined. Results: We found multiple significant correlations between DNA methylation and chemosensitivity. A potentially important association was observed for TREX1, which encodes the 3′ exonuclease I that serves as a STING antagonist in the regulation of a cytosolic DNA-sensing pathway. Increased methylation and low expression of TREX1 were associated with the sensitivity to Aurora kinase inhibitors AZD-1152, SCH-1473759, SNS-314, and TAK-901; the CDK inhibitor R-547; the Vertex ATR inhibitor Cpd 45; and the mitotic spindle disruptor vinorelbine. Compared with cell lines of other cancer types, TREX1 had low mRNA expression and increased upstream region methylation in SCLC, suggesting a possible relationship with SCLC sensitivity to Aurora kinase inhibitors. We also identified multiple additional correlations indicative of potential mechanisms of chemosensitivity. Methylation of the 3′UTR of CEP350 and MLPH, involved in centrosome machinery and microtubule tracking, respectively, was associated with response to Aurora kinase inhibitors and other agents. EPAS1 methylation was associated with response to Aurora kinase inhibitors, a PLK-1 inhibitor and a Bcl-2 inhibitor. KDM1A methylation was associated with PLK-1 inhibitors and a KSP inhibitor. Increased promoter methylation of SLFN11 was correlated with resistance to DNA damaging agents, as a result of low or no SLFN11 expression. The 5′ UTR of the epigenetic modifier EZH2 was associated with response to Aurora kinase inhibitors and a FGFR inhibitor. Methylation and expression of YAP1 were correlated with response to an mTOR inhibitor. Among nonneuroendocrine markers, EPHA2 was associated with response to Aurora kinase inhibitors and a PLK-1 inhibitor and CD151 with Bcl-2 inhibitors.

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Section: Discussionsupporting

confidence: 91%

Epigenome-wide DNA methylation analysis of small cell lung cancer cell lines suggests potential chemotherapy targets

et al. 2020

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“…Although we found no signi cant correlation between SLFN11 expression and other clinicopathological variables (Table 3), SLFN11 expression levels tended to be lower in older patients. A previous report suggested that high levels of methylation of SLFN11 were signi cantly associated with older age (32). Bioinformatics analysis using CellMinerCDB (https://discover.nci.nih.gov/cellminercdb/) demonstrated a strong inverse correlation between SLFN11 methylation in promoter regions and its mRNA expression level (r = -0.750, p = 0.00013; Figure S2) (30,31).…”

Section: Slfn11 Expression and Agementioning

confidence: 74%

The First Evidence for SLFN11 Expression As An Independent Prognostic Factor for Patients with Esophageal Cancer After Chemoradiotherapy

Kagami

Yamade

Suzuki

et al. 2020

Preprint

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Abstract Background:Schlafen 11 (SLFN11) was recently identified as a dominant determinant of sensitivity to DNA-targeting agents including platinum-based drugs. SLFN11 also reportedly enhances cellular radiosensitivity. In this study, we examined the prognostic value of SLFN11 expression in esophageal squamous cell carcinoma (ESCC) patients treated with definitive chemoradiotherapy (dCRT), including the platinum derivative nedaplatin.Methods:Seventy-three patients with ESCC who received dCRT were examined. SLFN11 expression was analyzed using immunohistochemistry and evaluated using a histo-score (H-score). Correlation between the H-score and overall survival was analyzed. An H-score ≥ 51 was provisionally defined as indicating high SLFN11 expression.Results:High SLFN11 expression was independently associated with better prognosis in ESCC patients (hazard ratio = 0.295, 95% CI = 0.143–0.605, p = 0.001 for multivariate analysis). Kaplan-Meier survival curves showed that the prognostic value of high SLFN11 expression was most evident in patients at clinical stages II and III (p = 0.004).Conclusion:SLFN11 expression is an independent prognostic factor for ESCC patients treated with dCRT and a potential biomarker for treatment selection of ESCC. Examination of SLFN11 may be particularly useful for clinical Stage II–III patients who wish to choose dCRT (instead of surgery) to preserve esophageal function.

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“…This may also be relevant to ICF syndrome patients with HELLS mutations, given that hypomethylation of repeat sequences is observed at a subset of chromosomes and the most frequently observed mutations in ICF syndrome are within DNMT3b (Hansen et al, 1999;Jin et al, 2008). In addition, HELLS has been associated with hypomethylation of specific repeat elements in some colorectal tumours and loss of DNA methylation has been linked to metastasis (Samuelsson et al, 2016;He et al, 2017). However, DNA methylation does not occur in budding yeast and consequently it seems likely to be the function at heterochromatic regions or DNA repair that is conserved in the yeast homolog, Irc5.…”

Section: Discussionmentioning

confidence: 99%

The human HELLS chromatin remodelling protein promotes end resection to facilitate homologous recombination within heterochromatin

Kollárovič

Topping

Shaw

et al. 2018

Preprint

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Efficient double-strand break repair in eukaryotes requires manipulation of chromatin structure. ATP-dependent chromatin remodelling enzymes can facilitate different DNA repair pathways, during different stages of the cell cycle and in a range of chromatin environments. The contribution of remodelling factors to break repair within heterochromatin during G2 is unclear. The human HELLS protein is a Snf2-like chromatin remodeller family member and is mutated or misregulated in several cancers and some cases of ICF syndrome. HELLS has been implicated in the DNA damage response, but its mechanistic function in repair is not well understood. We find that HELLS facilitates homologous recombination at two-ended breaks within heterochromatic regions during G2. HELLS enables end-resection and accumulation of CtIP at IR-induced foci. We identify an interaction between HELLS and CtIP and establish that the ATPase domain of HELLS is required to promote DSB repair. This function of HELLS in maintenance of genome stability is likely to contribute to its role in cancer biology and demonstrates that different chromatin remodelling activities are required for efficient repair in specific genomic contexts.

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Methylation of SLFN11 is a Marker of Poor Prognosis and Cisplatin Resistance in Colorectal Cancer

Abstract: SLFN11 is frequently methylated in human CRC, and the expression of SLFN11 is regulated by promoter region methylation. Methylation of SLFN11 reduced the sensitivity of CRC cells to cisplatin.

Cited by 48 publications

References 24 publications

Epigenome-wide DNA methylation analysis of small cell lung cancer cell lines suggests potential chemotherapy targets

Epigenome-wide DNA methylation analysis of small cell lung cancer cell lines suggests potential chemotherapy targets

The First Evidence for SLFN11 Expression As An Independent Prognostic Factor for Patients with Esophageal Cancer After Chemoradiotherapy

The human HELLS chromatin remodelling protein promotes end resection to facilitate homologous recombination within heterochromatin

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