Comprehensive analysis of regulation of DNA methyltransferase isoforms in human breast tumors

Hegde, Mangala; Joshi, Manjunath B.

doi:10.1007/s00432-021-03519-4

Cited by 25 publications

(22 citation statements)

References 327 publications

(349 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The earlier reports have shown that the aberrant DNA methylation activity of DNMT3B is linked to the development and progression of breast cancer ( 35 , 57 ). Nonetheless, the mechanisms of DNMT3B-mediated DNA hypermethylation remain obscure.…”

Section: Discussionmentioning

confidence: 99%

27-Hydroxycholesterol, The Estrogen Receptor Modulator, Alters DNA Methylation in Breast Cancer

2022

View full text Add to dashboard Cite

27-hydroxycholesterol (27-HC) is the first known endogenous selective estrogen receptor modulator (SERM), and its elevation from normal levels is closely associated with breast cancer. A plethora of evidence suggests that aberrant epigenetic signatures in breast cancer cells can result in differential responses to various chemotherapeutics and often leads to the development of resistant cancer cells. Such aberrant epigenetic changes are mostly dictated by the microenvironment. The local concentration of oxygen and metabolites in the microenvironment of breast cancer are known to influence the development of breast cancer. Hence, we hypothesized that 27-HC, an oxysterol, which has been shown to induce breast cancer progression via estrogen receptor alpha (ERα) and liver X receptor (LXR) and by modulating immune cells, may also induce epigenetic changes. For deciphering the same, we treated the estrogen receptor-positive cells with 27-HC and identified DNA hypermethylation on a subset of genes by performing DNA bisulfite sequencing. The genes that showed significant DNA hypermethylation were phosphatidylserine synthase 2 (PTDSS2), MIR613, indoleamine 2,3-dioxygenase 1 (IDO1), thyroid hormone receptor alpha (THRA), dystrotelin (DTYN), and mesoderm induction early response 1, family member 3 (MIER). Furthermore, we found that 27-HC weakens the DNMT3B association with the ERα in MCF-7 cells. This study reports that 27-HC induces aberrant DNA methylation changes on the promoters of a subset of genes through modulation of ERα and DNMT3B complexes to induce the local DNA methylation changes, which may dictate drug responses and breast cancer development.

show abstract

Section: Discussionmentioning

confidence: 99%

27-Hydroxycholesterol, The Estrogen Receptor Modulator, Alters DNA Methylation in Breast Cancer

2022

View full text Add to dashboard Cite

show abstract

“…DNMTs are a family of enzymes that catalyze the reaction of addition of the methyl group to cytosine residues within CpG dinucleotides using S-adenosylmethionine as a methyl donor. A recent analysis of regulation of DNA methyltransferase isoforms in human breast tumors revealed that DNMT1, DNMT3A, and DNMT3B promoters harbor multiple ERα-binding sites [154].…”

Section: Epigenetics As Unifying Mechanismmentioning

confidence: 99%

“…breast tumors revealed that DNMT1, DNMT3A, and DNMT3B promoters harbor multiple ERα-binding sites [154]. A sex bias in DNA methylation levels, usually associated with sex-biased gene expression, was found in many animal and human studies [155][156][157].…”

Section: Epigenetics As Unifying Mechanismmentioning

confidence: 99%

Gender Specific Differences in Disease Susceptibility: The Role of Epigenetics

2021

View full text Add to dashboard Cite

Many complex traits or diseases, such as infectious and autoimmune diseases, cancer, xenobiotics exposure, neurodevelopmental and neurodegenerative diseases, as well as the outcome of vaccination, show a differential susceptibility between males and females. In general, the female immune system responds more efficiently to pathogens. However, this can lead to over-reactive immune responses, which may explain the higher presence of autoimmune diseases in women, but also potentially the more adverse effects of vaccination in females compared with in males. Many clinical and epidemiological studies reported, for the SARS-CoV-2 infection, a gender-biased differential response; however, the majority of reports dealt with a comparable morbidity, with males, however, showing higher COVID-19 adverse outcomes. Although gender differences in immune responses have been studied predominantly within the context of sex hormone effects, some other mechanisms have been invoked: cellular mosaicism, skewed X chromosome inactivation, genes escaping X chromosome inactivation, and miRNAs encoded on the X chromosome. The hormonal hypothesis as well as other mechanisms will be examined and discussed in the light of the most recent epigenetic findings in the field, as the concept that epigenetics is the unifying mechanism in explaining gender-specific differences is increasingly emerging.

show abstract

“…DNA methylation is well-studied epigenetic modification that plays a key role in the regulation of gene expression ( 1 ). In mammals, DNA methylation primarily occurs within CpGs and is catalytically executed by a family of enzymes called DNA methyltransferases, DNMTs, which are classified as either maintenance or de novo methyltransferases ( 2 ) Maintenance methyltransferase DNMT1, maintains DNA methylation pattern during replication throughout the life of an organism, whereas de novo methyltransferases DNMT3a and DNMT3b establish methylation pattern during gametogenesis. With S-adenosylmethionine (SAM) acting as a methyl donor, DNMTs catalyze the addition of a methyl group to the fifth carbon of the cytosine residue ring of a CpG dinucleotide, generating 5-methylcytosine ( 3 , 4 ).…”

Section: Introductionmentioning

confidence: 99%

“…The DNA methylation function of DNMT1 is reported to be modulated by post-translational modifications, which include phosphorylation, ubiquitination, methylation and acetylation ( 2 ). Mass spectrometry analyses indicate that human DNMT1 activity is regulated at the post-translational level through phosphorylation at the N-terminal domain ( 2 ), and phosphorylation by kinases Akt and PKC at this domain resulted in disruption of DNMT1 interaction with its partners and promoted global hypomethylation ( 11 ). Phosphorylation of DNMT1 at the C-terminal domain influenced the abundance and activity of DNMT1 ( 2 ).…”

Section: Introductionmentioning

confidence: 99%

Re-Expression of ERα and AR in Receptor Negative Endocrine Cancers via GSK3 Inhibition

et al. 2022

View full text Add to dashboard Cite

DNA methylation, catalyzed by DNA methyltransferase (DNMT), is a well-characterized epigenetic modification in cancer cells. In particular, promoter hypermethylation of AR and ESR1 results in loss of expression on Androgen Receptor (AR) and Estrogen Receptor (ER), respectively, and is associated with a hormone refractory state. We now report that Glycogen Synthase Kinase 3 (GSK3) phosphorylates DNMT1 at S714, which is localized to a 62 amino acid region referred to as auto-inhibitory linker, which functions to occlude the DNA from the active site of DNMT1 to prevent the methylation of unmethylated DNA. Molecular Dynamics simulation indicates that phosphorylation at S714 resulted in conformational rearrangement of the autoinhibitory domain that inactivated its ability to block the methylation of unmethylated DNA and resulted in enhanced DNA binding. Treatment with a novel and more selective inhibitor of GSK3 resulted in decreased methylation of the promoter region of genes encoding the Androgen Receptor (AR) and Estrogen Receptor alpha (ERa) and re-expression of the AR and ERa in AR negative prostate cancer and ER negative breast cancer cells, respectively. As a result, concurrent treatment with the GSK3 inhibitor resulted in responsiveness of AR negative prostate cancer and ER negative breast cancer cells to inhibitors of the AR or ER, respectively, in in vitro and in vivo experimental models.

show abstract

Comprehensive analysis of regulation of DNA methyltransferase isoforms in human breast tumors

Cited by 25 publications

References 327 publications

27-Hydroxycholesterol, The Estrogen Receptor Modulator, Alters DNA Methylation in Breast Cancer

27-Hydroxycholesterol, The Estrogen Receptor Modulator, Alters DNA Methylation in Breast Cancer

Gender Specific Differences in Disease Susceptibility: The Role of Epigenetics

Re-Expression of ERα and AR in Receptor Negative Endocrine Cancers via GSK3 Inhibition

Contact Info

Product

Resources

About