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

Jy, Chuang; Lo, W-L; Ko, C-Y; Chou, Szu Yi; Chen, R-M; Chang, Kai Yen; Hung, Jan Jong; Su, W.; Chang, Wing Chung; Hsu, Todd

doi:10.1038/oncsis.2017.31

Cited by 41 publications

(45 citation statements)

References 70 publications

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“…Sp1 is a transcription factor that plays a central role in regulating the expression of genes associated with pro-oncogenic activity [20]. Thus, attenuation of Sp1 expression by BA may alter the expression of various genes that regulate the malignant behaviors of GBM cells.…”

Section: Ba Treatment Alters Expression Of Er Stress-related Genesmentioning

confidence: 99%

Betulinic Acid-Mediated Tuning of PERK/CHOP Signaling by Sp1 Inhibition as a Novel Therapeutic Strategy for Glioblastoma

Hsu

Yang

et al. 2020

Cancers

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Patients with glioblastoma are at high risk of local recurrences after initial treatment with standard therapy, and recurrent tumor cells appear to be resistant to first-line drug temozolomide. Thus, finding an effective second-line agent for treating primary and recurrent glioblastomas is critical. Betulinic acid (BA), a natural product of plant origin, can cross the blood–brain barrier. Here, we investigated the antitumor effects of BA on typical glioblastoma cell lines and primary glioblastoma cells from patients, as well as corresponding temozolomide-resistant cells. Our findings verified that BA significantly reduced growth in all examined cells. Furthermore, gene-expression array analysis showed that the unfolded-protein response was significantly affected by BA. Moreover, BA treatment increased activation of the protein kinase RNA-like endoplasmic reticulum kinase (PERK)/C/EBP homologous protein (CHOP) apoptotic pathway, and reduced specificity protein 1 (Sp1) expression. However, Sp1 overexpression reversed the observed cell-growth inhibition and PERK/CHOP signaling activation induced by BA. Because temozolomide-resistant cells exhibited significantly increased Sp1 expression, we concluded that Sp1-mediated PERK/CHOP signaling inhibition protects glioblastoma against cancer therapies; hence, BA treatment targeting this pathway can be considered as an effective therapeutic strategy to overcome such chemoresistance and tumor relapse.

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Section: Ba Treatment Alters Expression Of Er Stress-related Genesmentioning

confidence: 99%

Betulinic Acid-Mediated Tuning of PERK/CHOP Signaling by Sp1 Inhibition as a Novel Therapeutic Strategy for Glioblastoma

Hsu

Yang

et al. 2020

Cancers

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“…The encoded protein is involved in many cellular processes, including cell differentiation, cell growth, apoptosis, immune responses, response to DNA damage, and chromatin remodeling. According to reports, SP1 plays important role in the tumorigenesis, progression, and drug resistance of gliomas [22][23][24][25]. We found that the promoter region of miR-4310 also contains GC-rich fragments.…”

Section: Sp1 Induces the Expression Of Mir-4310 By Binding To Its Promentioning

confidence: 77%

MiR-4310 induced by SP1 targets PTEN to promote glioma progression

Zhiyong

Jie

Huang

et al. 2020

Preprint

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Background: miRNAs have been reported to be involved in multiple biological processes of gliomas. Here, we aimed to analyze miR-4310 and its correlation genes involved in the tumor progression of human glioma. Methods: miR-4310 expression levels were examined in glioma and non-tumor brain (NB) tissues. The molecular mechanisms of miR-4310 expression and its effects on cell proliferation, migration, and invasion were explored by 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) , Transwell chamber, Boyden chamber, and western blot analyses, as well as in vivo tumorigenesis in nude mice. The relationships among miR-4310, SP1, and phosphatase and tensin homolog (PTEN) were explored by chromatin immunoprecipitation (ChIP), agarose gel electrophoresis, electrophoresis mobility shift (EMSA), and dual luciferase reporter gene assays. Results: miR-4310 expression was upregulated in glioma tissues compared to NB. Overexpressed miR-4310 promoted glioma cell proliferation, migration, and invasion in vitro and tumorigenesis in vivo . Inhibition of miR-4310 was sufficient to reverse these results. Mechanistic analyses revealed that miR-4310 promoted glioma progression through the PI3K/AKT pathway by targeting PTEN. Additionally, SP1 induced the expression of miR-4310 by binding to its promoter region. Conclusion: miR-4310 promotes the progression of glioma by targeting PTEN and activating the PI3K/AKT pathway meanwhile the expression of miR-4310 is induced by SP1.

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“…Indeed, SP1 binding has already been reported to be insensitive to methylation [42,43]. Of note, intrinsic demethylation activity has been associated with SP1 binding due to DNMT3a inhibition [44]. It may enhance the parity-induced demethylation process, thus enabling better p53 binding to this site.…”

Section: Discussionmentioning

confidence: 99%

H2AX Promoter Demethylation at Specific Sites Plays a Role in STAT5-Induced Tumorigenesis

Havusha-Laufer

Kosenko

Kisliouk

et al. 2020

J Mammary Gland Biol Neoplasia

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Deregulated STAT5 activity in the mammary gland of transgenic mice results in parity-dependent latent tumorigenesis. The trigger for cell transformation was previously associated with hyperactivation of the H2AX proximal promoter in a small basal cell population during pregnancy. The current study focuses on the latent activation of tumor development. H2AX was highly expressed in carcinoma and adenocarcinoma as compared to the multiparous mammary gland, whereas pSTAT5 expression decreased in a tumor type-dependent manner. In contrast to the pregnant gland, no positive correlation between H2AX and pSTAT5 expression could be defined in carcinoma and adenocarcinoma. Using targeted methylation analysis, the methylation profile of the H2AX promoter was characterized in the intact gland and tumors. Average H2AX promoter methylation in the tumors was relatively high (~90%), but did not exceed that of the multiparous gland; 5mC methylation was higher in the differentiated tumors and negatively correlated with its oxidative product 5hmC and H2AX expression. Individual analysis of 25 H2AX promoter-methylation sites revealed two consecutive CpGs at positions −77 and − 54 that were actively demethylated in the multiparous gland, but not in their age-matched virgin counterpart. The different methylation profiles at these sites distinguished tumor types and may assume a prognostic role. In-silico and ChIP analyses revealed overlapping methylationindependent SP1-binding and methylation-dependent p53-binding to these sites. We propose that interference with SP1-assisted p53-binding to these sites abrogates H2AX's ability to arrest the cell cycle upon DNA damage, and contributes to triggering latent development of STAT5-induced tumors in estrapausal multiparous mice. Keywords Cancer. H2AX. Mammary gland. Methylation. STAT5 Abbreviations DDR DNA-damage response GFP Green fluorescent protein Obs/Exp Observed to expected STAT Signal transducer and activator of transcription TET Ten-eleven translocation protein 5mC 5 methylcytosine 5hmC 5 hydroxymethylcytosine 5caC 5-carboxylcytosine 5fC 5-formylcytosine

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

Cited by 41 publications

References 70 publications

Betulinic Acid-Mediated Tuning of PERK/CHOP Signaling by Sp1 Inhibition as a Novel Therapeutic Strategy for Glioblastoma

Betulinic Acid-Mediated Tuning of PERK/CHOP Signaling by Sp1 Inhibition as a Novel Therapeutic Strategy for Glioblastoma

MiR-4310 induced by SP1 targets PTEN to promote glioma progression

H2AX Promoter Demethylation at Specific Sites Plays a Role in STAT5-Induced Tumorigenesis

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