Epigenetic inactivation of DLC-1 in supratentorial primitive neuroectodermal tumor

Pang, Jesse Chung Sean; Chang, Qing; Chung, Yuk Fei; Teo, Jennifer; Poon, Wai Sang; Zhou, Liang; Kong, Xiangyin; Ng, Ho Keung

doi:10.1016/j.humpath.2004.09.021

Cited by 28 publications

(21 citation statements)

References 36 publications

(57 reference statements)

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“…Tumor suppressor genes that are down-regulated or silenced by promoter hypermethylation are often located in genomic regions of deletion (27). Undoubtedly, promoter hypermethylation or histone deacetylation are major mechanisms responsible for down-regulation or silencing of DLC-1 in a variety of solid tumors and hematological malignancies (28)(29)(30)(31)(32)(33)(34). Most likely, epigenetic modifications account for dysregulation of DLC-2 as well.…”

Section: Discussionmentioning

confidence: 99%

Expression profile of the tumor suppressor genes DLC-1 and DLC-2 in solid tumors

Ullmannova¹,

Popescu²

2006

Int J Oncol

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Abstract. Several years after the isolation of deleted in liver cancer 1 (DLC-1), a gene that encodes a Rho GTPase activating protein, the closely related DLC-2 gene was identified. DLC-1 and DLC-2 are ~50% identical and share the same SAM-RhoGAP-START domain organization. Since DLC-1 and -2 are located at chromosome regions that are commonly deleted in cancer cells and have been found to function as tumor suppressor genes, we sought to compare their expression profiles in several common types of cancer and to determine whether dlc1 and dlc2 proteins cooperate in tumor development. Using cancer-profiling arrays, we detected for the first time down-regulation of DLC-1 expression in renal, uterine and rectal cancers and down-regulation of DLC-2 expression in lung, ovarian, renal, breast, uterine, gastric, colon and rectal tumors. Since DLC-1 also functions as a metastasis suppressor gene in breast cancer, DLC-1 and DLC-2 expression were examined in a series of primary ductal carcinomas derived from patients with regional lymph node metastases. Using quantitative RT-PCR we detected a significantly lower expression of DLC-1 and DLC-2 in high percentage of tumors, suggesting that deficiency of either DLC gene facilitates dissemination of breast carcinoma cells to secondary sites. We examined DLC-2 expression in DLC-1-negative cell lines derived from human breast, non-small cell lung, and hepatocellular carcinomas, that could be rendered less or non-tumorigenic by ectopic expression of DLC-1. DLC-2 transcripts were detected in all cell lines, indicating that none of the cells were deficient in both members of the DLC family. This comparative expression analysis of DLC-1 and -2 identifies down-regulation of the two emerging bona fide tumor suppressor genes in additional types of solid tumors. The large spectrum of cancers with dysregulated DLC genes underlines the involvement of this family of genes in cancer development.

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Section: Discussionmentioning

confidence: 99%

Expression profile of the tumor suppressor genes DLC-1 and DLC-2 in solid tumors

Ullmannova¹,

Popescu²

2006

Int J Oncol

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“…44,119 Inda et al 64 analyzed the methylation status of primary intracranial PNETs and found higher promoter hypermethylation of p14/ARF (a gene located at the CDK2A locus on 9p21) in supratentorial PNETs than in medulloblastoma. Pang et al 113 described CpG island hypermethylation of the tumor suppressor gene DLC-1 in a subset of supratentorial PNETs. Another study showed the induction of cell death in a caspase-dependent manner by HDAC inhibitors in supratentorial PNET cell lines.…”

Section: Supratentorial Pnetsmentioning

confidence: 99%

Epigenetic mechanisms regulating neural development and pediatric brain tumor formation

Faria

Rutka

Smith

et al. 2011

PED

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Pediatric brain tumors are the leading cause of cancer-related death in children, and among them, embryonal tumors represent the largest group with an associated poor prognosis and long-term morbidity for survivors. The field of cancer epigenetics has emerged recently as an important area of investigation and causation of a variety of neoplasms, and is defined as alterations in gene expression without changes in DNA sequence. The best studied epigenetic modifications are DNA methylation, histone modifications, and RNA-based mechanisms. These modifications play an important role in normal development and differentiation but their dysregulation can lead to altered gene function and cancer. In this review the authors describe the mechanisms of normal epigenetic regulation, how they interplay in neuroembryogenesis, and how these can cause brain tumors in children when dysregulated. The potential use of epigenetic markers to design more effective treatment strategies for children with malignant brain tumors is also discussed.

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“…Gene silencing by promoter methylation has been detected in RASSF1A for both tumors [19,51], whereas HIC1 [19] and DLC1 [52] hypermethylation has been observed exclusively in ependymoma and sPNETs, respectively. Recently, p14/ARF-a region also shown to be inactivated through genetic deletions in sPNETs [26•]-was shown to be hypermethylated and silenced in sPNETs with a greater frequency than in medulloblastomas and ependymomas [53].…”

Section: Epigenetics Of Pediatric Neoplasmsmentioning

confidence: 99%

The Genetics of Pediatric Brain Tumors

Dubuc

Northcott

Mack

et al. 2010

Curr Neurol Neurosci Rep

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Brain tumors are the most common childhood solid malignancy and the leading cause of cancer-related death in children. Medulloblastoma, ependymoma, supratentorial primitive neuroectodermal tumors, and pilocytic astrocytoma are the most prevalent types, all of which are clinically, histologically, and genetically heterogeneous. Despite an incomplete molecular understanding of these tumors, we have made significant headway in the past 5 years in identifying and classifying important genetic alterations and pathways central to the disease process. This review summarizes our current state of knowledge, emphasizes recent seminal findings in the field, and proposes future research efforts needed to further characterize the genetic basis of pediatric brain tumors.

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Epigenetic inactivation of DLC-1 in supratentorial primitive neuroectodermal tumor

Cited by 28 publications

References 36 publications

Expression profile of the tumor suppressor genes DLC-1 and DLC-2 in solid tumors

Expression profile of the tumor suppressor genes DLC-1 and DLC-2 in solid tumors

Epigenetic mechanisms regulating neural development and pediatric brain tumor formation

The Genetics of Pediatric Brain Tumors

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