Prognostic significance of DAPK and RASSF1A promoter hypermethylation in non-small cell lung cancer (NSCLC).

Niklińska, Wiesława; Naumnik, Wojciech; Sulewska, Anetta; Kozłowski, Mirosław; Pankiewicz, Walentyn; Milewski, Robert

doi:10.2478/v10042-009-0091-2

Cited by 39 publications

(25 citation statements)

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“…In the study of stage I lung cancer patients mentioned above, DNA methylation of RASSF1 , a ras-associated putative tumor suppressor, was also found to be associated with recurrence [58]. Numerous groups have reported RASSF1 DNA methylation in lung cancer [37], [96]–[98], and methylation of this gene has been associated with poor prognosis [96], [99] and later stage cancer [100]. The latter observations would appear to be in agreement with our characterization of RASSF1 DNA methylation as associated with the transition from in situ cancer to invasive cancer.…”

Section: Discussionmentioning

confidence: 99%

DNA Methylation Changes in Atypical Adenomatous Hyperplasia, Adenocarcinoma In Situ, and Lung Adenocarcinoma

et al. 2011

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BackgroundAberrant DNA methylation is common in lung adenocarcinoma, but its timing in the phases of tumor development is largely unknown. Delineating when abnormal DNA methylation arises may provide insight into the natural history of lung adenocarcinoma and the role that DNA methylation alterations play in tumor formation.Methodology/Principal FindingsWe used MethyLight, a sensitive real-time PCR-based quantitative method, to analyze DNA methylation levels at 15 CpG islands that are frequently methylated in lung adenocarcinoma and that we had flagged as potential markers for non-invasive detection. We also used two repeat probes as indicators of global DNA hypomethylation. We examined DNA methylation in 249 tissue samples from 93 subjects, spanning the putative spectrum of peripheral lung adenocarcinoma development: histologically normal adjacent non-tumor lung, atypical adenomatous hyperplasia (AAH), adenocarcinoma in situ (AIS, formerly known as bronchioloalveolar carcinoma), and invasive lung adenocarcinoma. Comparison of DNA methylation levels between the lesion types suggests that DNA hypermethylation of distinct loci occurs at different time points during the development of lung adenocarcinoma. DNA methylation at CDKN2A ex2 and PTPRN2 is already significantly elevated in AAH, while CpG islands at 2C35, EYA4, HOXA1, HOXA11, NEUROD1, NEUROD2 and TMEFF2 are significantly hypermethylated in AIS. In contrast, hypermethylation at CDH13, CDX2, OPCML, RASSF1, SFRP1 and TWIST1 and global DNA hypomethylation appear to be present predominantly in invasive cancer.Conclusions/SignificanceThe gradual increase in DNA methylation seen for numerous loci in progressively more transformed lesions supports the model in which AAH and AIS are sequential stages in the development of lung adenocarcinoma. The demarcation of DNA methylation changes characteristic for AAH, AIS and adenocarcinoma begins to lay out a possible roadmap for aberrant DNA methylation events in tumor development. In addition, it identifies which DNA methylation changes might be used as molecular markers for the detection of preinvasive lesions.

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Section: Discussionmentioning

confidence: 99%

DNA Methylation Changes in Atypical Adenomatous Hyperplasia, Adenocarcinoma In Situ, and Lung Adenocarcinoma

et al. 2011

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“…There are few reports regarding disease prognosis and gene methylation in lung squamous cell carcinoma [13-16]. The clinical outcome among patients with lung squamous cell carcinoma is improved by Gemcitabine [17], while Pemetrexed is particularly active in non-squamous NSCLC histology [18], and it is now clear that chemosensitivity differs according to histology.…”

Section: Discussionmentioning

confidence: 99%

Aberrant methylation of N-methyl-D-aspartate receptor type 2B (NMDAR2B) in non-small cell carcinoma

et al. 2011

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BackgroundN-methyl-D-aspartate receptors (NMDAR) act as tumor suppressors of digestive malignancies. The expression and genetic methylation patterns of NMDAR2B in non-small cell lung cancer (NSCLC) are unknown.MethodsThe relationship between gene methylation and expression of NMDAR2B was analyzed in NSCLC cell lines (N = 9) and clinical tissues (N = 216). The cell lines were studied using RT-PCR and 5-aza-2'-deoxycytidine treatment, while the clinical tissues were examined by methylation specific real-time quantitative PCR and immunohistochemistry. Retrospective investigation of patient records was used to determine the clinical significance of NMDAR2B methylation.ResultsNMDAR2B was silenced in five of the nine cell lines; 5-aza-2'-deoxycytidine treatment restored expression, and was inversely correlated with methylation. Aberrant methylation of NMDAR2B, detected in 61% (131/216) of clinical NSCLC tissues, was inversely correlated with the status of protein expression in 20 randomly examined tumors. Aberrant methylation was not associated with clinical factors such as gender, age, histological type, or TNM stage. However, aberrant methylation was an independent prognostic factor in squamous cell carcinoma cases.ConclusionsAberrant methylation of the NMDAR2B gene is a common event in NSCLC. The prognosis was significantly better for cases of squamous cell carcinoma in which NMDAR2B was methylated. It may have different roles in different histological types.

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“…Loss of DAPK kinase function, rather than lack of protein expression, is also found in renal cell carcinoma (RCC), lung cancer, and other types of cancer (26)(27)(28). Posttranslational modification, such as S308 phosphorylation of DAPK, may be one of the reasons for the loss of tumor-suppressor function in cancers with DAPK expression.…”

Section: Introductionmentioning

confidence: 99%

Novel Cancer Therapeutics with Allosteric Modulation of the Mitochondrial C-Raf–DAPK Complex by Raf Inhibitor Combination Therapy

et al. 2015

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Mitochondria are the powerhouses of cells. Mitochondrial CRaf is a potential cancer therapeutic target, as it regulates mitochondrial function and is localized to the mitochondria by its Nterminal domain. However, Raf inhibitor monotherapy can induce S338 phosphorylation of C-Raf (pC-Raf S338 ) and impede therapy. This study identified the interaction of C-Raf with S308 phosphorylated DAPK (pDAPK S308 ), which together became colocalized in the mitochondria to facilitate mitochondrial remodeling. Combined use of the Raf inhibitors sorafenib and GW5074 had synergistic anticancer effects in vitro and in vivo, but targeted mitochondrial function, rather than the canonical Raf signaling pathway. C-Raf depletion in knockout MEF C-RafÀ/À or siRNA knockdown ACHN renal cancer cells abrogated the cytotoxicity of combination therapy. Crystal structure simulation showed that GW5074 bound to C-Raf and induced a C-Raf conformational change that enhanced sorafenib-binding affinity.In the presence of pDAPK S308 , this drug-target interaction compromised the mitochondrial targeting effect of the N-terminal domain of C-Raf, which induced two-hit damages to cancer cells. First, combination therapy facilitated pC-Raf S338 and pDAPK S308 translocation from mitochondria to cytoplasm, leading to mitochondrial dysfunction and reactive oxygen species (ROS) generation. Second, ROS facilitated PP2A-mediated dephosphorylation of pDAPK S308 to DAPK. PP2A then dissociated from the C-Raf-DAPK complex and induced profound cancer cell death. Increased pDAPK S308 modification was also observed in renal cancer tissues, which correlated with poor disease-free survival and poor overall survival in renal cancer patients. Besides mediating the anticancer effect, pDAPK S308 may serve as a predictive biomarker for Raf inhibitors combination therapy, suggesting an ideal preclinical model that is worthy of clinical translation. Cancer Res; 75(17); 3568-82. Ó2015 AACR.

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Prognostic significance of DAPK and RASSF1A promoter hypermethylation in non-small cell lung cancer (NSCLC).

Cited by 39 publications

References 19 publications

DNA Methylation Changes in Atypical Adenomatous Hyperplasia, Adenocarcinoma In Situ, and Lung Adenocarcinoma

DNA Methylation Changes in Atypical Adenomatous Hyperplasia, Adenocarcinoma In Situ, and Lung Adenocarcinoma

Aberrant methylation of N-methyl-D-aspartate receptor type 2B (NMDAR2B) in non-small cell carcinoma

Novel Cancer Therapeutics with Allosteric Modulation of the Mitochondrial C-Raf–DAPK Complex by Raf Inhibitor Combination Therapy

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