TET2-mediated epigenetic reprogramming of breast cancer cells impairs lysosome biogenesis

Laurent, Audrey; Madigou, Thierry; Bizot, Maud; Turpin, Marion; Palierne, Gaëlle; Mahé, Elise A.; Guimard, Sarah; Métivier, Raphaël; Avner, Stéphane; Péron, Christine Le; Salbert, Gilles

doi:10.26508/lsa.202101283

Cited by 3 publications

(4 citation statements)

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“…S4A-B), suggesting a general tendency toward reprogramming of the cancer methylome. We then examined the binding activities of known regulators of DNA methylation, namely, DNMT1, DNMT3B, and TET2, at the DMPs [ 32 , 40 ]. Of the three genes, TET2-binding activity was selectively enriched at Hypo-DMPs in MCF-7 cells (Additional file 1 : Fig.…”

Section: Resultsmentioning

confidence: 99%

“…To investigate the relationships between DMPs and DNA methyltransferases and demethylating enzymes, we obtained ChIP-seq data for DNMT3A and DNMT3B (HepG2) from ENCODE and published ChIP-seq data for TET2 (MCF7) [ 32 ]. We obtained multiple independent datasets of FOXA1 binding from ChIP-Seq experiments, including four cancer cell lines (A549, HepG2, and MCF-7 from ENCODE and T47D [ 33 ]) and tissues (colorectal cancer and breast cancer) [ 34 , 35 ].…”

Section: Methodsmentioning

confidence: 99%

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Conserved methylation signatures associate with the tumor immune microenvironment and immunotherapy response

Qin,

Zhou,

Guo

et al. 2024

Genome Med

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Background Aberrant DNA methylation is a major characteristic of cancer genomes. It remains unclear which biological processes determine epigenetic reprogramming and how these processes influence the variants in the cancer methylome, which can further impact cancer phenotypes. Methods We performed pairwise permutations of 381,900 loci in 569 paired DNA methylation profiles of cancer tissue and matched normal tissue from The Cancer Genome Atlas (TCGA) and defined conserved differentially methylated positions (DMPs) based on the resulting null distribution. Then, we derived independent methylation signatures from 2,465 cancer-only methylation profiles from the TCGA and 241 cell line-based methylation profiles from the Genomics of Drug Sensitivity in Cancer (GDSC) cohort using nonnegative matrix factorization (NMF). We correlated DNA methylation signatures with various clinical and biological features, including age, survival, cancer stage, tumor immune microenvironment factors, and immunotherapy response. We inferred the determinant genes of these methylation signatures by integrating genomic and transcriptomic data and evaluated the impact of these signatures on cancer phenotypes in independent bulk and single-cell RNA/methylome cohorts. Results We identified 7,364 differentially methylated positions (2,969 Hyper-DMPs and 4,395 Hypo-DMPs) in nine cancer types from the TCGA. We subsequently retrieved three highly conserved, independent methylation signatures (Hyper-MS1, Hypo-MS1, and Hypo-MS4) from cancer tissues and cell lines based on these Hyper and Hypo-DMPs. Our data suggested that Hypo-MS4 activity predicts poor survival and is associated with immunotherapy response and distant tumor metastasis, and Hypo-MS4 activity is related to TP53 mutation and FOXA1 binding specificity. In addition, we demonstrated a correlation between the activities of Hypo-MS4 in cancer cells and the fractions of regulatory CD4 + T cells with the expression levels of immunological genes in the tumor immune microenvironment. Conclusions Our findings demonstrated that the methylation signatures of distinct biological processes are associated with immune activity in the cancer microenvironment and predict immunotherapy response.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Conserved methylation signatures associate with the tumor immune microenvironment and immunotherapy response

Qin,

Zhou,

Guo

et al. 2024

Genome Med

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“…S10). A previous report showed that IRF9 can be induced by decitabine and TET2-catalytic domain [ 42 ], so there is a large possibility that IRF9 could also be induced by 5-azacytidine and vitamin C combination treatment. In addition, a positive feedback loop between IFR9 and STING has also been reported by Ma et al [ 43 ].…”

Section: Discussionmentioning

confidence: 99%

Epigenetic priming improves salvage chemotherapy in diffuse large B-cell lymphoma via endogenous retrovirus-induced cGAS-STING activation

Min

Kim

et al. 2023

Clin Epigenet

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Background Although most patients with diffuse large B-cell lymphoma (DLBCL) achieve complete remission after first-line rituximab-containing immunochemotherapy, up to 40% of patients relapse and require salvage therapy. Among those patients, a substantial proportion remain refractory to salvage therapy due to insufficient efficacy or intolerance of toxicities. A hypomethylating agent, 5-azacytidine, showed a chemosensitizing effect when primed before chemotherapy in lymphoma cell lines and newly diagnosed DLBCL patients. However, its potential to improve outcomes of salvage chemotherapy in DLBCL has not been investigated. Results In this study, we demonstrated the mechanism of 5-azacytidine priming as a chemosensitizer in a platinum-based salvage regimen. This chemosensitizing effect was associated with endogenous retrovirus (ERV)-induced viral mimicry responses via the cGAS-STING axis. We found deficiency of cGAS impaired the chemosensitizing effect of 5-azacytidine. Furthermore, combining vitamin C and 5-azacytidine to synergistically activate STING could be a potential remedy for insufficient priming induced by 5-azacytidine alone. Conclusions Taken together, the chemosensitizing effect of 5-azacytidine could be exploited to overcome the limitations of the current platinum-containing salvage chemotherapy in DLBCL and the status of cGAS-STING has the potential to predict the efficacy of 5-azacytidine priming.

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“…Over-expression of TET2 Catalytic Domain (TET2-CD) increases the 5hmC levels, which induces and inhibits the expression of thousands of genes that inhibit cell proliferation and migration in MCF-7 BC cells, as well as tumor growth in vivo. Interestingly, TET2-CD alters the 5hmC in binding sites for the V-Myc Avian Myelocytomatosis Viral Oncogene Homolog (MYC) transcription factor in a set of genes involved in lysosome biogenesis [ 81 ]. On the other hand, TET2 knockout decreases the 5hmC levels and increases the 5mC levels, particularly in enhancers, altering the expression of genes, including ERα target genes, by reducing the ERα transcription factor binding.…”

Section: Molecular Mechanisms Of Tet Enzymes In Bcmentioning

confidence: 99%

TET Enzymes and 5hmC Levels in Carcinogenesis and Progression of Breast Cancer: Potential Therapeutic Targets

Salmerón-Bárcenas,

Zacapala-Gómez,

Torres-Rojas

et al. 2023

IJMS

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Breast Cancer (BC) was the most common female cancer in incidence and mortality worldwide in 2020. Similarly, BC was the top female cancer in the USA in 2022. Risk factors include earlier age at menarche, oral contraceptive use, hormone replacement therapy, high body mass index, and mutations in BRCA1/2 genes, among others. BC is classified into Luminal A, Luminal B, HER2-like, and Basal-like subtypes. These BC subtypes present differences in gene expression signatures, which can impact clinical behavior, treatment response, aggressiveness, metastasis, and survival of patients. Therefore, it is necessary to understand the epigenetic molecular mechanism of transcriptional regulation in BC, such as DNA demethylation. Ten-Eleven Translocation (TET) enzymes catalyze the oxidation of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) on DNA, which in turn inhibits or promotes the gene expression. Interestingly, the expression of TET enzymes as well as the levels of the 5hmC epigenetic mark are altered in several types of human cancers, including BC. Several studies have demonstrated that TET enzymes and 5hmC play a key role in the regulation of gene expression in BC, directly (dependent or independent of DNA de-methylation) or indirectly (via interaction with other proteins such as transcription factors). In this review, we describe our recent understanding of the regulatory and physiological function of the TET enzymes, as well as their potential role as biomarkers in BC biology.

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TET2-mediated epigenetic reprogramming of breast cancer cells impairs lysosome biogenesis

Cited by 3 publications

References 100 publications

Conserved methylation signatures associate with the tumor immune microenvironment and immunotherapy response

Conserved methylation signatures associate with the tumor immune microenvironment and immunotherapy response

Epigenetic priming improves salvage chemotherapy in diffuse large B-cell lymphoma via endogenous retrovirus-induced cGAS-STING activation

TET Enzymes and 5hmC Levels in Carcinogenesis and Progression of Breast Cancer: Potential Therapeutic Targets

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