Methylation of RASSF1A gene promoter is regulated by p53 and DAXX

Zhang, Hailong; He, Jing; Li, Jiansha; Tian, Dan; Gu, Liqun; Zhou, Mi

doi:10.1096/fj.12-215491

Cited by 41 publications

(39 citation statements)

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“…It was shown recently that RASSF1A promoter methylation is regulated by p53 and deathassociated protein 6 (DAXX) [151]. The authors have found that p53 binds to the RASSF1A promoter, recruits DAXX and DNMT1, leading to DNA methylation and subsequently to inactivation of RASSF1A.…”

Section: Thementioning

confidence: 99%

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RASSF tumor suppressor gene family: Biological functions and regulation

et al. 2014

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a b s t r a c tGenetic changes through allelic loss and nucleic acid or protein modifications are the main contributors to loss of function of tumor suppressor proteins. In particular, epigenetic silencing of genes by promoter hypermethylation is associated with increased tumor severity and poor survival. The RASSF (Ras association domain family) family of proteins consists of 10 members, many of which are tumor suppressor proteins that undergo loss of expression through promoter methylation in numerous types of cancers such as leukemia, melanoma, breast, prostate, neck, lung, brain, colorectal and kidney cancers. In addition to their tumor suppressor function, RASSF proteins act as scaffolding agents in microtubule stability, regulate mitotic cell division, modulate apoptosis, control cell migration and cell adhesion, and modulate NFjB activity and the duration of inflammation. The ubiquitous functions of these proteins highlight their importance in numerous physiological pathways. In this review, we will focus on the biological roles of the RASSF family members and their regulation.

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Section: Thementioning

confidence: 99%

“…Interestingly, fluctuation in p53 protein levels did not affect the rates of RASSF1A methylation. Conversely, methylation of the RASSF1A promoter was critically controlled by DAXX, as the enforced overexpression of DAXX led to enhanced RASSF1A promoter methylation, whereas inhibition of DAXX reduced RASS-F1A methylation [151].…”

Section: Thementioning

confidence: 99%

RASSF tumor suppressor gene family: Biological functions and regulation

et al. 2014

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“…On the other hand, DAXX regulates transcription of mammalian and viral genes via its ability to interact with a number of transcription factors [for more details see (Preston and Nicholl, 2006; Saffert and Kalejta, 2006; Salomoni and Khelifi, 2006; Lindsay et al, 2008; Lukashchuk and Everett, 2010; Tsai et al, 2011; Rivera-Molina et al, 2012; Glass and Everett, 2013; Schreiner et al, 2013; Shalginskikh et al, 2013)] and epigenetic regulators. In particular, DAXX interacts with HDAC-II (Hollenbach et al, 2002), acetyltransferases (CBP) (Kuo et al, 2005), and DNA methyltransferase (Dnmt1) (Puto and Reed, 2008; Zhang et al, 2013), suggesting an important role in chromatin remodeling.…”

Section: The Pml-interacting Protein Daxx Is a Chaperone For The Histmentioning

confidence: 99%

The PML-Interacting Protein DAXX: Histone Loading Gets into the Picture

Salomoni¹

2013

Front. Oncol.

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The promyelocytic leukemia (PML) protein has been implicated in regulation of multiple key cellular functions, from transcription to calcium homeostasis. PML pleiotropic role is in part related to its ability to localize to both the nucleus and cytoplasm. In the nucleus, PML is known to regulate gene transcription, a role linked to its ability to associate with transcription factors as well as chromatin-remodelers. A new twist came from the discovery that the PML-interacting protein death-associated protein 6 (DAXX) acts as chaperone for the histone H3.3 variant. H3.3 is found enriched at active genes, centromeric heterochromatin, and telomeres, and has been proposed to act as important carrier of epigenetic information. Our recent work has implicated DAXX in regulation of H3.3 loading and transcription in the central nervous system (CNS). Remarkably, driver mutations in H3.3 and/or its loading machinery have been identified in brain cancer, thus suggesting a role for altered H3.3 function/deposition in CNS tumorigenesis. Aberrant H3.3 deposition may also play a role in leukemia pathogenesis, given DAXX role in PML-RARα-driven transformation and the identification of a DAXX missense mutation in acute myeloid leukemia. This review aims to critically discuss the existing literature and propose new avenues for investigation.

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“…The RASSF1 gene encodes several isoforms, including RASSF1A , RASSF1B , and RASSF1C , all of which are generated from alternative mRNA splicing and promoter usage[15]. RASSF1A transcriptional silencing is frequently observed feature in multiple types of cancer as a result of promoter hypermethylation; however, few reports are available describing the mechanisms underlying this phenomenon[16–19]. RASSF1A transcription is suppressed by hypermethylation in breast, ovarian, gastric, nasopharyngeal, and bladder cancers as well as neuroblastoma and renal cell lines[20–25].…”

Section: Introductionmentioning

confidence: 99%

Epigenetic reactivation of RASSF1A by phenethyl isothiocyanate (PEITC) and promotion of apoptosis in LNCaP cells

Boyanapalli

Fuentes

et al. 2016

Pharmacological Research

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Epigenetic silencing of tumor suppressor genes is a phenomenon frequently observed in multiple cancers. Ras-association domain family 1 isoform A (RASSF1A) is a well-characterized tumor suppressor that belongs to the Ras-association domain family. Several studies have demonstrated that hypermethylation of the RASSF1A promoter is frequently observed in lung, prostate, and breast cancers. Phenethyl isothiocyanate (PEITC), a phytochemical abundant in cruciferous vegetables, possesses chemopreventive activities; however, its potential involvement in epigenetic mechanisms remains elusive. The present study aimed to examine the role of PEITC in the epigenetic reactivation of RASSF1A and the induction of apoptosis in LNCaP cells. LNCaP cells were treated for 5 days with 0.01% DMSO, 2.5 or 5 μM PETIC or 2.5 μM azadeoxycytidine (5-Aza) with 0.5 μM trichostatin A (TSA). We evaluated the effects of these treatments on CpG demethylation using methylation-specific polymerase chain reaction (MSP) and bisulfite genomic sequencing (BGS). CpG demethylation was significantly enhanced in cells treated with 5 μM PEITC and 5-Aza+TSA; therefore, the latter treatment was used as a positive control in subsequent experiments. The decrease in RASSF1A promoter methylation correlated with an increase in expression of the RASSF1A gene in a dose-dependent manner. To confirm that promoter demethylation was mediated by DNA methyltransferases (DNMTs), we analyzed the expression levels of DNMTs and histone deacetylases (HDACs) at the gene and protein levels. PEITC reduced DNMT1, 3A and 3B protein levels in a dose-dependent manner, and 5 μM PEITC significantly reduced DNMT3A and 3B protein levels. HDAC1, 2, 4 and 6 protein expression was also inhibited by 5 μM PEITC. The combination of 5-Aza and TSA, a DNMT inhibitor and a HDAC inhibitor, respectively, was used as a positive control as this treatment significantly inhibited both HDACs and DNMTs. The function of RASSF1A reactivation in promoting apoptosis and inducing G2/M cell cycle arrest was analyzed using flow-cytometry analysis with Annexin V and propidium iodide (PI). Growth inhibition effect on LNCaP cells were investigated by colony formation assay. In addition, we analyzed p21, caspase-3 and 7, Bax, and Cyclin B1 protein levels. Flow-cytometry analysis of cells stained with PI alone demonstrated that 5 μM PEITC promotes early apoptosis and G2/M cell cycle arrest. Flow cytometry analysis of cells stained with Annexin V and PI also demonstrated an increased proportion of cells in early apoptosis in cells treated with 5 μM PEITC or 5-Aza with TSA. PEITC and efficiently inhibit colony numbers and total area. In addition, 5 μM PEITC significantly enhanced p21, caspase-3, 7 and Bax levels and reduced Cyclin B1 expression compared with the control group. Collectively, the results of our study suggest that PEITC induces apoptosis in LNCaP cells potentially by reactivating RASSF1A via epigenetic mechanisms.

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Methylation of RASSF1A gene promoter is regulated by p53 and DAXX

Cited by 41 publications

References 41 publications

RASSF tumor suppressor gene family: Biological functions and regulation

RASSF tumor suppressor gene family: Biological functions and regulation

The PML-Interacting Protein DAXX: Histone Loading Gets into the Picture

Epigenetic reactivation of RASSF1A by phenethyl isothiocyanate (PEITC) and promotion of apoptosis in LNCaP cells

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