Epigenetic silencing of tumor suppressor genes: Paradigms, puzzles, and potential

Kazanets, Anna; Shorstova, Tatiana; Hilmi, Khalid; Marques, Maud; Witcher, Michael

doi:10.1016/j.bbcan.2016.04.001

Cited by 137 publications

(126 citation statements)

References 215 publications

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“…While the ultimate effects of many such mutations are not yet clear, their prominence indicates a central role for epigenomic dysregulation in oncogenesis [94, 98]. The most well established epigenetic changes are promoter hypermethylation and associated silencing of tumor suppressor genes [95, 99, 100] as well as genome-wide DNA hypomethylation [101–103]. Hypomethylation of ERVs and L1s in many tumors has been documented [104–106] and general transcriptional up-regulation of ERVs and L1s is often observed in cancers [33, 107–109].…”

Section: Introductionmentioning

confidence: 99%

Endogenous retroviral promoter exaptation in human cancer

2016

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Cancer arises from a series of genetic and epigenetic changes, which result in abnormal expression or mutational activation of oncogenes, as well as suppression/inactivation of tumor suppressor genes. Aberrant expression of coding genes or long non-coding RNAs (lncRNAs) with oncogenic properties can be caused by translocations, gene amplifications, point mutations or other less characterized mechanisms. One such mechanism is the inappropriate usage of normally dormant, tissue-restricted or cryptic enhancers or promoters that serve to drive oncogenic gene expression. Dispersed across the human genome, endogenous retroviruses (ERVs) provide an enormous reservoir of autonomous gene regulatory modules, some of which have been co-opted by the host during evolution to play important roles in normal regulation of genes and gene networks. This review focuses on the “dark side” of such ERV regulatory capacity. Specifically, we discuss a growing number of examples of normally dormant or epigenetically repressed ERVs that have been harnessed to drive oncogenes in human cancer, a process we term onco-exaptation, and we propose potential mechanisms that may underlie this phenomenon.

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Section: Introductionmentioning

confidence: 99%

Endogenous retroviral promoter exaptation in human cancer

2016

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“…Thus, epigenetic changes, especially the methylation of CpG islands in the promoters of tumor suppressor genes, may cause gene silencing and the onset of tumors [15, 16]. …”

Section: Introductionmentioning

confidence: 99%

Dickkopf-Related Protein 2 is Epigenetically Inactivated and Suppresses Colorectal Cancer Growth and Tumor Metastasis by Antagonizing Wnt/β-Catenin Signaling

Wang

Yue

Shao

et al. 2017

Cell Physiol Biochem

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Background/Aims: Aberrant activation of the Wnt/β-catenin signaling pathway plays a key role in the pathogenesis of multiple tumors including digestive cancers. Recent studies have reported that Dickkopf-related protein 2 (DKK2) is epigenetically inactivated in numerous types of cancers and that its gene products exhibit tumor-suppressive properties. However, the biological functions and underlying molecular mechanisms of DKK2 in colon carcinoma remains obscure. Methods: We examined the expression of DKK2 in colon tumor cell lines by RT-PCR and its promoter methylation status in colon tumor cell lines and primary tumors by methylation-specific PCR (MSP). Ectopic expression of DKK2 was measured by RT-PCR prior to the other experiments. To investigate the function of DKK2, we assayed colony formation and cell proliferation, utilized flow cytometric analyses of the cell cycle and acridine orange/ethidium bromide (AO/EB) fluorescence staining for apoptosis, and examined wound healing, transwell migration and tumor growth in vivo. Western blots were used to explore the mechanisms of DKK2 in epithelial- mesenchymal transition and canonical Wnt/β-catenin signaling. Results: We show here that downregulation or silencing of DKK2 was closely associated with the hypermethylation status of its promoter and that DKK2 expression could be restored by demethylation treatment. Methylation of the DKK2 promoter was detected in nearly all tumors and tumor-adjacent tissues, but not in normal colon tissues. Ectopic expression of DKK2 in colon cell lines HCT116 and HT-29 inhibited colony formation and cell viability by inducing cell cycle G0/G1 arrest and apoptosis, and growth of stable DKK2-infected HCT116 cells in nude mice was decreased compared to controls. Furthermore, DKK2 restrained cell migration through partial reversal of epithelial-to- mesenchymal transition and also by downregulating several stem cell markers. Our data further showed that restoration of DKK2 expression resulted in downregulation of active β-catenin and its downstream target genes. Conclusion: DKK2 appears to be a functional tumor suppressor regulating tumorigenesis of colorectal cancer by antagonizing Wnt/β-catenin signaling.

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“…In metastatic breast cancer, endothelial growth factor receptor endocytosis was suppressed, leading to EZH2 overexpression through up-regulation of the MEK-ERK-Elk-1 pathway (21), with subsequent effects of the up-regulated EZH2 on cancer proliferation. EZH2 has also been shown to repress the expression of classic tumor suppressor genes such as CDKN2A and p53 (22) directly, and to reduce the levels of RAD51 leading to the activation of Raf1/ERK and β-catenin signalling (23). Several reports have revealed that EZH2 affects not only genetic but also epigenetic pathways.…”

Section: Discussionmentioning

confidence: 99%