EMT is associated with an epigenetic signature of ECM remodeling genes

Peixoto, Paul; Etcheverry, Amandine; Aubry, Marc; Missey, Anaïs; Lachat, Camille; Perrard, Jérôme; Hendrick, Elodie; Delage-Mourroux, Régis; Mosser, Jean; Borg, Christophe; Feugeas, Jean-Paul; Herfs, Michaël; Boyer-Guittaut, Michaël; Hervouet, Éric

doi:10.1038/s41419-019-1397-4

Cited by 105 publications

(82 citation statements)

References 35 publications

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“…The EMT process not only changes the cellular characteristics of cancer cells from an epithelial to mesenchymal phenotype, but also triggers remodeling of the extracellular matrix by activating various proteases such as the MMPs, thereby achieving anoikis resistance, and increased invasiveness and migration (24). MMPs are a group of enzymes that regulate the extracellular matrix.…”

Section: Discussionmentioning

confidence: 99%

DCST1-AS1 Promotes TGF-β-Induced Epithelial–Mesenchymal Transition and Enhances Chemoresistance in Triple-Negative Breast Cancer Cells via ANXA1

Tang

Chen²,

Chen

et al. 2020

Front. Oncol.

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Triple-negative breast cancer (TNBC) is a highly metastatic breast cancer subtype, and the primary systemic treatment strategy involves conventional chemotherapy. DC-STAMP domain containing 1-antisense 1 (DCST1-AS1) is a long non-coding RNA that promotes TNBC migration and invasion. Studying the role of DCST1-AS1 in promoting epithelial-mesenchymal transition (EMT) and chemoresistance will provide a new strategy for TNBC therapy. In the present study, we found that DCST1-AS1 regulates the expression or secretion of EMT-related proteins E-cadherin, snail family zinc finger 1 (SNAI1), vimentin, matrix metallopeptidase 2 (MMP2), and matrix metallopeptidase 9 (MMP9). Interference with DCST1-AS1 impaired TGF-β-induced TNBC cell invasion and migration. DCST1-AS1 directly binds to ANXA1 in BT-549 cells and affects the expression of ANXA1. DCST1-AS1 enhances TGF-β/Smad signaling in BT-549 cells through ANXA1 to promote EMT. The combination of DCST1-AS1 and ANXA1 also contributes to enhancement of the resistance of BT-549 cells to doxorubicin and paclitaxel. In conclusion, DCST1-AS1 promotes TGF-β-induced EMT and enhances chemoresistance in TNBC cells through ANXA1, and therefore represents a potentially promising target for metastatic breast cancer therapy.

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Section: Discussionmentioning

confidence: 99%

DCST1-AS1 Promotes TGF-β-Induced Epithelial–Mesenchymal Transition and Enhances Chemoresistance in Triple-Negative Breast Cancer Cells via ANXA1

Tang

Chen²,

Chen

et al. 2020

Front. Oncol.

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“…These findings suggest that hyperacetylation of histone H3 and H3K9 might be involved in gene transcription regulation. Interestingly, histone acetylation was shown to be involved in transcriptional regulation of EMT-related genes and associated pathways [36][37][38], and lactate increases H3K9ac mark, as well as global histone acetylation [17].…”

Section: Discussionmentioning

confidence: 99%

Lactate Increases Renal Cell Carcinoma Aggressiveness through Sirtuin 1-Dependent Epithelial Mesenchymal Transition Axis Regulation

Miranda‐Gonçalves

Lameirinhas

Macedo-Silva

et al. 2020

Cells

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Background: Renal cell carcinoma (RCC) displays a glycolytic phenotype (Warburg effect). Increased lactate production, impacting on tumor biology and microenvironment modulation, has been implicated in epigenetic mechanisms' regulation, leading to histone deacetylases inhibition. Thus, in-depth knowledge of lactate's impact on epigenome regulation of highly glycolytic tumors might allow for new therapeutic strategies. Herein, we investigated how extracellular lactate affected sirtuin 1 activity, a class III histone deacetylase (sirtuins, SIRTs) in RCC. Methods: In vitro and in vivo interactions between lactate and SIRT1 in RCC were investigated in normal kidney and RCC cell lines. Finally, SIRT1 and N-cadherin immunoexpression was assessed in human RCC and normal renal tissues. Results: Lactate inhibited SIRT1 expression in normal kidney and RCC cells, increasing global H3 and H3K9 acetylation. Cells exposed to lactate showed increased cell migration and invasion entailing a mesenchymal phenotype. Treatment with a SIRT1 inhibitor, nicotinamide (NAM), paralleled lactate effects, promoting cell aggressiveness. In contrast, alpha-cyano-4-hydroxycinnamate (CHC), a lactate transporter inhibitor, reversed them by blocking lactate transport. In vivo (chick chorioallantoic membrane (CAM) assay), lactate and NAM exposure were associated with increased tumor size and blood vessel recruitment, whereas CHC displayed the opposite effect. Moreover, primary RCC revealed N-cadherin upregulation whereas SIRT1 expression levels were downregulated compared to normal tissues. Conclusions: In RCC, lactate enhanced aggressiveness and modulated normal kidney cell phenotype, in part through downregulation of SIRT1, unveiling tumor metabolism as a promising therapeutic target.

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“…The ECM is a key non‐cellular component of TME and acts as a barrier to tumourigenesis . The EMT is an indispensable biological process in cancer progression by which the epithelial‐derived malignant cells acquire the ability to migrate and invade . The degradation of ECM and induction of EMT are necessary for tumour invasion and metastasis.…”

Section: Tert Promotes Tumour Invasion and Metastasismentioning

confidence: 99%

Role of telomerase in the tumour microenvironment

Liu

Guo

Liu

et al. 2019

Clin Exp Pharma Physio

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The tumour mass is an organ-like structure consisting of cancer cells and their directly associated microenvironment. The tumour microenvironment (TME) is the local environment where malignant cells strive and survive, and is composed of cancers cells and their surroundings such as blood vessels, extracellular matrix (ECM), infiltrating immune cells, fibroblasts, and signalling molecules. 1,2 In addition, cancer stem cells (CSCs) and endoplasmic reticulum (ER) stress influence the properties of the TME to benefit tumour cell growth. 3,4 The cross-talk between the cancer cells and their environment involves numerous oncogenic transcription factors. These factors are aberrantly reactivated and trigger a series of cellular events such as genome instability, reprogrammed metabolism, infinite proliferation, angiogenesis, invasion and metastasis, immune cell infiltration, and enhanced inflammation, all of which have been widely recognized as the characteristics of cancer. Telomeres consist of a non-coding DNA tandem repeat of sequence 5′-TTAGGG-3′, located at the ends of the linear eukaryotic chromosomes. 26,27 Due to "the end replication problem", the telomeres shorten with each round of DNA replication. Once their lengths shorten to a certain level, the cells may undergo replicative senescence. 26,28 Telomerase is an RNA-dependent DNA polymerase that synthesizes telomeric DNA sequences and maintains the telomere length, providing the immortal cells with the molecular basis for unlimited proliferation potential. Human telomerase essentially AbstractTelomeres are specialized genomic structures that protect chromosomal ends to maintain genomic stability. Telomeric length is primarily regulated by the telomerase complex, essentially consisting of an RNA template (TERC), an enzymatic subunit (telomerase reverse transcriptase, TERT). In humans, telomerase activity is repressed during embryonic differentiation and is absent in most somatic cells. However, it is upregulated or reactivated in 80%-90% of the primary tumours in humans. The human TERT (hTERT) plays a pivotal role in cellular immortality and tumourigenesis.However, the molecular mechanisms of telomerase functioning in cancer have not been fully understood beyond the telomere maintenance. Several research groups, including ours, have demonstrated that hTERT possesses vital functions independent of its telomere maintenance, including angiogenesis, inflammation, cancer cell stemness, and epithelial-mesenchymal transformation (EMT). All these telomereindependent activities of hTERT may contribute to the regulation of the dynamics and homeostasis of the tumour microenvironment (TME), thereby promoting tumour growth and development. Cancer progression and metastasis largely depend upon the interactions between cancer cells and their microenvironment. In this review, the involvement of TERT in the tumour microenvironment and the underlying implications in cancer therapeutics have been summarized. K E Y W O R D Sangiogenesis, inflammation, telomerase, TERT, tumour micro...

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EMT is associated with an epigenetic signature of ECM remodeling genes

Cited by 105 publications

References 35 publications

DCST1-AS1 Promotes TGF-β-Induced Epithelial–Mesenchymal Transition and Enhances Chemoresistance in Triple-Negative Breast Cancer Cells via ANXA1

DCST1-AS1 Promotes TGF-β-Induced Epithelial–Mesenchymal Transition and Enhances Chemoresistance in Triple-Negative Breast Cancer Cells via ANXA1

Lactate Increases Renal Cell Carcinoma Aggressiveness through Sirtuin 1-Dependent Epithelial Mesenchymal Transition Axis Regulation

Role of telomerase in the tumour microenvironment

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