Stimulation of ribosomal RNA gene promoter by transcription factor Sp1 involves active DNA demethylation by Gadd45-NER pathway

Rajput, Pallavi; Pandey, Vijaya; Kumar, Vijay

doi:10.1016/j.bbagrm.2016.05.002

Cited by 9 publications

(7 citation statements)

References 56 publications

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“…28, 29 Similar results are shown in Figure 4c: Sp1-binding to the CYP17A1 promoter gradually increased after inhibition of DNA methylation. Interestingly, Sp1 is involved in ribosomal DNA demethylation in ribosome biogenesis, 56 but it is unclear how Sp1 causes DNA demethylation. Here, we identified a possible mechanism.…”

Section: Discussionmentioning

confidence: 99%

Upregulation of CYP17A1 by Sp1-mediated DNA demethylation confers temozolomide resistance through DHEA-mediated protection in glioma

et al. 2017

Oncogenesis

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Steroidogenesis-mediated production of neurosteroids is important for brain homeostasis. Cytochrome P450 17A1 (CYP17A1), which converts pregnenolone to dehydroepiandrosterone (DHEA) in endocrine organs and the brain, is required for prostate cancer progression and acquired chemotherapeutic resistance. However, whether CYP17A1-mediated DHEA synthesis is involved in brain tumor malignancy, especially in glioma, the most prevalent brain tumor, is unknown. To investigate the role of CYP17A1 in glioma, we determined that CYP17A1 expression is significantly increased in gliomas, which secrete more DHEA than normal astrocytes. We found that as gliomas became more malignant, both CYP17A1 and DHEA were significantly upregulated in temozolomide (TMZ)-resistant cells and highly invasive cells. In particular, the increase of CYP17A1 was caused by Sp1-mediated DNA demethylation, whereby Sp1 competed with DNMT3a for binding to the CYP17A1 promoter in TMZ-resistant glioma cells. CYP17A1 was required for the development of glioma cell invasiveness and resistance to TMZ-induced cytotoxicity. In addition, DHEA markedly attenuated TMZ-induced DNA damage and apoptosis. Together, our results suggest that components of the Sp1–CYP17A1–DHEA axis, which promotes the development of TMZ resistance, may serve as potential biomarkers and therapeutic targets in recurrent glioma.

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Section: Discussionmentioning

confidence: 99%

Upregulation of CYP17A1 by Sp1-mediated DNA demethylation confers temozolomide resistance through DHEA-mediated protection in glioma

et al. 2017

Oncogenesis

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“…However, in response to DNA damage, Sp1 is phosphorylated and recruited to the sites of DNA double-strand breaks where it possibly mediates the recruitment of chromatin remodeling factors involved in the repair of these breaks [ 165 ]. Sp1 can define the binding of Gadd45A at a specific site of DNA damage [ 166 ]. Sp1 is a specificity protein that belongs to the family of Krüppel transcription factors (Sp/KLF), which currently has 26 members [ 167 ].…”

Section: Participation Of Transcription Factors In the Mechanism Omentioning

confidence: 99%

Roles of Histone Deacetylases and Inhibitors in Anticancer Therapy

Verza

Das

Fachin

et al. 2020

Cancers

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Histones are the main structural proteins of eukaryotic chromatin. Histone acetylation/ deacetylation are the epigenetic mechanisms of the regulation of gene expression and are catalyzed by histone acetyltransferases (HAT) and histone deacetylases (HDAC). These epigenetic alterations of DNA structure influence the action of transcription factors which can induce or repress gene transcription. The HATs catalyze acetylation and the events related to gene transcription and are also responsible for transporting newly synthesized histones from the cytoplasm to the nucleus. The activity of HDACs is mainly involved in silencing gene expression and according to their specialized functions are divided into classes I, II, III and IV. The disturbance of the expression and mutations of HDAC genes causes the aberrant transcription of key genes regulating important cancer pathways such as cell proliferation, cell-cycle regulation and apoptosis. In view of their role in cancer pathways, HDACs are considered promising therapeutic targets and the development of HDAC inhibitors is a hot topic in the search for new anticancer drugs. The present review will focus on HDACs I, II and IV, the best known inhibitors and potential alternative inhibitors derived from natural and synthetic products which can be used to influence HDAC activity and the development of new cancer therapies.

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“…Many reports have highlighted important roles for GADD45A in the DNA damage response and its ability to stimulate DNA repair. It enhances nucleotide excision repair (NER) by recruiting XPG, a component of the NER complex (Smith et al 1994;Tran et al 2002;Barreto et al 2007;Rajput et al 2016), and base excision repair (BER) through recruitment of apurinic endonuclease 1 (APE1), thymine DNA glycosylase (TDG), and the deaminase AID , members of the BER complex.…”

Section: Gadd45 In Dna Repair and Demethylationmentioning

confidence: 99%

“…Additionally, there is accumulating evidence that a NER-or BER-like process is involved in removal of DNA methylation, an epigenetic marker associated with the repression of transcriptional initiation. The long noncoding RNA (lncRNA) TARID directs GADD45A to the TCF21 promoter (Arab et al 2014), the tumor suppressor protein ING1 recruits GADD45A to tri-methylated histone 3 lysine 4 residues (Schäfer et al 2013), and the transcription factors TAF12 and SP1 recruit GADD45A to the promoter of ribosomal genes (Schmitz et al 2009;Rajput et al 2016). Once recruited to the DNA, GADD45A has a role in then recruiting either the BER or NER complex to facilitate DNA demethylation (Arab et al 2014;Rajput et al 2016).…”

Section: Gadd45 In Dna Repair and Demethylationmentioning

confidence: 99%

Gaba

2018

Encyclopedia of Signaling Molecules

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G alpha o 1893G regulators of the Gao protein may provide a cellspecific mechanism for Gao-regulated signaling pathways. PTX catalyzes the ADP-ribosylation of the a subunits of the Go, Gi, and Gt proteins at the C-terminal cysteine residue (À4 position). This prevents the G protein from interacting with GPCRs on the cell membrane, thus interfering with intracellular signaling. 1896 G alpha o G alpha o 1897 G cyclase, guanylate cyclase, Rap1 GTPaseactivating protein (Rap1GAP), axin, and pins. Compartmentalization of these signaling molecules in membrane rafts may ensure specificity and fidelity in Gao signaling. Go is the most abundant G protein in the central nervous system, where it comprises about 1% of membrane proteins in the mammalian brain. Go regulates neuronal development, memory, visual reception, olfactory reception, and taste reception. It is also localized in heart tissue and implicated in heart contractility. Its expression is regulated during the development of the brain and heart. Somatic mutations in the GNAO1 gene induce human cancers by rendering Gao constitutively activated. Heterozygous mutations in the GNAO1 gene cause epileptic encephalopathy by destabilizing Gao. Gao-deficient mice have several neurological deficits, including tremors, seizures, hyperalgesia, motor control impairment, and olfactory impairment. Muscarinic regulation of heart rate and heart rate variability is also impaired in Gao-deficient mice. Drosophila melanogaster mutants with loss of function of Gao show impaired morphogenesis of the heart and epithelial polarity of cardiac cells and abnormal sleep. Gao-deficient C. elegans has phenotypes including neuronal migration defects, hyperactive locomotion, and egg laying.

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Stimulation of ribosomal RNA gene promoter by transcription factor Sp1 involves active DNA demethylation by Gadd45-NER pathway

Cited by 9 publications

References 56 publications

Upregulation of CYP17A1 by Sp1-mediated DNA demethylation confers temozolomide resistance through DHEA-mediated protection in glioma

Upregulation of CYP17A1 by Sp1-mediated DNA demethylation confers temozolomide resistance through DHEA-mediated protection in glioma

Roles of Histone Deacetylases and Inhibitors in Anticancer Therapy

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