Functional antagonism of chromatin modulators regulates epithelial-mesenchymal transition

Epithelial-mesenchymal transition (EMT) is a developmental process hijacked by cancer cells to modulate proliferation, migration, and stress response. Whereas kinase signaling is believed to be an EMT driver, the molecular mechanisms underlying epithelial-mesenchymal interconversion are incompletely understood. Here, we show that the impact of chromatin regulators on EMT interconversion is broader than that of kinases. By combining pharmacological modulation of EMT, synthetic genetic tracing, and CRISPR interference screens, we uncovered a minority of kinases and several chromatin remodelers, writers, and readers governing homeostatic EMT in lung cancer cells. Loss of ARID1A, DOT1L, BRD2, and ZMYND8 had nondeterministic and sometimes opposite consequences on epithelial-mesenchymal interconversion. Together with RNAPII and AP-1, these antagonistic gatekeepers control chromatin of active enhancers, including pan-cancer-EMT signature genes enabling supraclassification of anatomically diverse tumors. Thus, our data uncover general principles underlying transcriptional control of cancer cell plasticity and offer a platform to systematically explore chromatin regulators in tumor-state–specific therapy.

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The epithelial-mesenchymal transcription factor SNAI1 represses transcription of the tumor suppressor miRNA let-7 in cancer

10.1101/2020.11.04.368688 ◽

2020 ◽

Author(s):

H Wang ◽

E Chirshev ◽

N Hojo ◽

T Suzuki ◽

A Bertucci ◽

...

Keyword(s):

Ovarian Cancer ◽

Transcription Factor ◽

Stem Cell ◽

Cancer Cells ◽

Molecular Mechanisms ◽

Epithelial Mesenchymal Transition ◽

Tumor Burden ◽

Cell Phenotype ◽

Mesenchymal Transition

AbstractWe aimed to determine the mechanism of epithelial-mesenchymal transition (EMT)-induced stemness in cancer cells. Cancer relapse and metastasis are caused by rare stem-like cells within tumors. Studies of stem cell reprogramming have linked let-7 repression and acquisition of stemness with the EMT factor, SNAI1. The mechanisms for the loss of let-7 in cancer cells are incompletely understood. In four carcinoma cell lines from breast cancer, pancreatic cancer and ovarian cancer and in ovarian cancer patient-derived cells, we analyzed stem cell phenotype and tumor growth via mRNA, miRNA, and protein expression, spheroid formation, and growth in patient-derived xenografts. We show that treatment with EMT-promoting growth factors or SNAI1 overexpression increased stemness and reduced let-7 expression, while SNAI1 knockdown reduced stemness and restored let-7 expression. Rescue experiments demonstrate that the pro-stemness effects of SNAI1 are mediated via let-7. In vivo, nanoparticle-delivered siRNA successfully knocked down SNAI1 in orthotopic patient-derived xenografts, accompanied by reduced stemness and increased let-7 expression, and reduced tumor burden. Chromatin immunoprecipitation demonstrated that SNAI1 binds the promoters of various let-7 family members, and luciferase assays revealed that SNAI1 represses let-7 transcription. In conclusion, the SNAI1/let-7 axis is an important component of stemness pathways in cancer cells, and this study provides a rationale for future work examining this axis as a potential target for cancer stem cell-specific therapies.Novelty and ImpactThis study provides new insight into molecular mechanisms by which EMT transcription factor SNAI1 exerts its pro-stemness effects in cancer cells, demonstrating its potential as a stem cell-directed target for therapy. In vitro and in vivo, mesoporous silica nanoparticle-mediated SNAI1 knockdown resulted in restoration of let-7 miRNA, inhibiting stemness and reducing tumor burden. Our studies validate in vivo nanoparticle-delivered RNAi targeting the SNAI1/let-7 axis as a clinically relevant approach.

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α-Mangostin Suppresses the Viability and Epithelial-Mesenchymal Transition of Pancreatic Cancer Cells by Downregulating the PI3K/Akt Pathway

BioMed Research International ◽

10.1155/2014/546353 ◽

2014 ◽

Vol 2014 ◽

pp. 1-12 ◽

Cited By ~ 27

Author(s):

Qinhong Xu ◽

Jiguang Ma ◽

Jianjun Lei ◽

Wanxing Duan ◽

Liang Sheng ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cancer Cells ◽

Molecular Mechanisms ◽

Epithelial Mesenchymal Transition ◽

Complementary Alternative Medicine ◽

Akt Pathway ◽

Migration And Invasion ◽

Mesenchymal Transition ◽

Matrigel Invasion ◽

Pancreatic Cancer Cells

α-Mangostin, a natural product isolated from the pericarp of the mangosteen fruit, has been shown to inhibit the growth of tumor cells in various types of cancers. However, the underlying molecular mechanisms are largely unclear. Here, we report thatα-mangostin suppressed the viability and epithelial-mesenchymal transition (EMT) of pancreatic cancer cells through inhibition of the PI3K/Akt pathway. Treatment of pancreatic cancer BxPc-3 and Panc-1 cells withα-mangostin resulted in loss of cell viability, accompanied by enhanced cell apoptosis, cell cycle arrest at G1 phase, and decrease of cyclin-D1. Moreover, Transwell and Matrigel invasion assays showed thatα-mangostin significantly reduced the migration and invasion of pancreatic cancer cells. Consistent with these results,α-mangostin decreased the expression of MMP-2, MMP-9, N-cadherin, and vimentin and increased the expression of E-cadherin. Furthermore, we found thatα-mangostin suppressed the activity of the PI3K/Akt pathway in pancreatic cancer cells as demonstrated by the reduction of the Akt phosphorylation byα-mangostin. Finally,α-mangostin significantly inhibited the growth of BxPc-3 tumor mouse xenografts. Our results suggest thatα-mangostin may be potentially used as a novel adjuvant therapy or complementary alternative medicine for the management of pancreatic cancers.

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Doxorubicin-Resistant TNBC Cells Exhibit Rapid Growth with Cancer Stem Cell-like Properties and EMT Phenotype, Which Can Be Transferred to Parental Cells through Autocrine Signaling

International Journal of Molecular Sciences ◽

10.3390/ijms222212438 ◽

2021 ◽

Vol 22 (22) ◽

pp. 12438

Author(s):

Anjugam Paramanantham ◽

Eun-Joo Jung ◽

Hye-Jung Kim ◽

Bae-Kwon Jeong ◽

Jin-Myung Jung ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Molecular Mechanisms ◽

Epithelial Mesenchymal Transition ◽

Morphological Changes ◽

Autocrine Signaling ◽

Mesenchymal Transition ◽

Doxorubicin Resistance ◽

Cancer Dormancy ◽

Resistance To Doxorubicin

Emerging evidence suggests that breast cancer stem cells (BCSCs), and epithelial–mesenchymal transition (EMT) may be involved in resistance to doxorubicin. However, it is unlear whether the doxorubicin-induced EMT and expansion of BCSCs is related to cancer dormancy, or outgrowing cancer cells with maintaining resistance to doxorubicin, or whether the phenotypes can be transferred to other doxorubicin-sensitive cells. Here, we characterized the phenotype of doxorubicin-resistant TNBC cells while monitoring the EMT process and expansion of CSCs during the establishment of doxorubicin-resistant MDA-MB-231 human breast cancer cells (DRM cells). In addition, we assessed the potential signaling associated with the EMT process and expansion of CSCs in doxorubicin-resistance of DRM cells. DRM cells exhibited morphological changes from spindle-shaped MDA-MB-231 cells into round-shaped giant cells. They exhibited highly proliferative, EMT, adhesive, and invasive phenotypes. Molecularly, they showed up-regulation of Cyclin D1, mesenchymal markers (β-catenin, and N-cadherin), MMP-2, MMP-9, ICAM-1 and down-regulation of E-cadherin. As the molecular mechanisms responsible for the resistance to doxorubicin, up-regulation of EGFR and its downstream signaling, were suggested. AKT and ERK1/2 expression were also increased in DRM cells with the advancement of resistance to doxorubicin. Furthermore, doxorubicin resistance of DRM cells can be transferred by autocrine signaling. In conclusion, DRM cells harbored EMT features with CSC properties possessing increased proliferation, invasion, migration, and adhesion ability. The doxorubicin resistance, and doxorubicin-induced EMT and CSC properties of DRM cells, can be transferred to parental cells through autocrine signaling. Lastly, this feature of DRM cells might be associated with the up-regulation of EGFR.

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Cellular and Molecular Mechanisms of Pristimerin in Cancer Therapy: Recent Advances

Frontiers in Oncology ◽

10.3389/fonc.2021.671548 ◽

2021 ◽

Vol 11 ◽

Author(s):

Run-Ze Chen ◽

Fei Yang ◽

Min Zhang ◽

Zhi-Gang Sun ◽

Nan Zhang

Keyword(s):

Chinese Medicine ◽

Traditional Chinese Medicine ◽

Cancer Cells ◽

Molecular Mechanisms ◽

Epithelial Mesenchymal Transition ◽

Quinone Methide ◽

Molecular Signaling ◽

Mesenchymal Transition ◽

Advantages And Disadvantages ◽

Anti Cancer

Seeking an efficient and safe approach to eliminate tumors is a common goal of medical fields. Over these years, traditional Chinese medicine has attracted growing attention in cancer treatment due to its long history. Pristimerin is a naturally occurring quinone methide triterpenoid used in traditional Chinese medicine to treat various cancers. Recent studies have identified alterations in cellular events and molecular signaling targets of cancer cells under pristimerin treatment. Pristimerin induces cell cycle arrest, apoptosis, and autophagy to exhibit anti-proliferation effects against tumors. Pristimerin also inhibits the invasion, migration, and metastasis of tumor cells via affecting cell adhesion, cytoskeleton, epithelial-mesenchymal transition, cancer stem cells, and angiogenesis. Molecular factors and pathways are associated with the anti-cancer activities of pristimerin. Furthermore, pristimerin reverses multidrug resistance of cancer cells and exerts synergizing effects with other chemotherapeutic drugs. This review aims to discuss the anti-cancer potentials of pristimerin, emphasizing multi-targeted biological and molecular regulations in cancers. Further investigations and clinical trials are warranted to understand the advantages and disadvantages of pristimerin treatment much better.

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Caffeic Acid Phenethyl Ester Inhibits Epithelial-Mesenchymal Transition of Human Pancreatic Cancer Cells

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2013/270906 ◽

2013 ◽

Vol 2013 ◽

pp. 1-7 ◽

Cited By ~ 5

Author(s):

Ming-Jen Chen ◽

Shou-Chuan Shih ◽

Horng-Yuan Wang ◽

Ching-Chung Lin ◽

Chia-Yuan Liu ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cancer Cells ◽

Caffeic Acid ◽

Molecular Mechanisms ◽

Epithelial Mesenchymal Transition ◽

Caffeic Acid Phenethyl Ester ◽

Human Pancreatic Cancer ◽

Mesenchymal Transition ◽

Pancreatic Cancer Cells ◽

Migration Potential

Background. This study aimed to investigate the effect of propolis component caffeic acid phenethyl ester (CAPE) on epithelial-mesenchymal transition (EMT) of human pancreatic cancer cells and the molecular mechanisms underlying these effects.Methods. The transforming growth factorβ(TGF-β-) induced EMT in human pancreatic PANC-1 cancer cells was characterized by observation of morphology and the expression of E-cadherin and vimentin by western blotting. The migration potential was estimated with wound closure assay. The expression of transcriptional factors was measured by quantitative RT-PCR and immunocytochemistry staining. The orthotopic pancreatic cancer xenograft model was used forin vivoassessment.Results. The overexpression of vimentin was attenuated by CAPE, and the alteration in morphology from polygonal to spindle shape was partially reversed by CAPE. Furthermore, CAPE delayed the TGF-β-stimulated migration potential. CAPE treatment did not reduce the expression levels of Smad 2/3, Snail 1, and Zeb 1 but inhibited the expression of transcriptional factor Twist 2. By using an orthotopic pancreatic cancer model, CAPE suppressed the expression of Twist 2 and growth of PANC-1 xenografts without significant toxicity.Conclusion. CAPE could inhibit the orthotopic growth and EMT of pancreatic cancer PANC-1 cells accompanied by downregulation of vimentin and Twist 2 expression.

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Yeast-Derived Recombinant Avenanthramides Inhibit Proliferation, Migration and Epithelial Mesenchymal Transition of Colon Cancer Cells

Nutrients ◽

10.3390/nu10091159 ◽

2018 ◽

Vol 10 (9) ◽

pp. 1159 ◽

Cited By ~ 5

Author(s):

Federica Finetti ◽

Andrea Moglia ◽

Irene Schiavo ◽

Sandra Donnini ◽

Giovanni Berta ◽

...

Keyword(s):

Colon Cancer ◽

Cancer Cells ◽

Cancer Cell ◽

Epithelial Mesenchymal Transition ◽

Antioxidant Properties ◽

Colon Cancer Cells ◽

Mesenchymal Transition ◽

Molecular Features ◽

Hydroxyanthranilic Acid ◽

The Impact

Avenanthramides (Avns), polyphenols found exclusively in oats, are emerging as promising therapeutic candidates for the treatment of several human diseases, including colon cancer. By engineering a Saccharomyces cerevisiae strain, we previously produced two novel phenolic compounds, N-(E)-p-coumaroyl-3-hydroxyanthranilic acid (Yeast avenanthramide I, YAvnI) and N-(E)-caffeoyl-3-hydroxyanthranilic acid (Yeast avenanthramide II, YAvnII), which are endowed with a structural similarity to bioactive oat avenanthramides and stronger antioxidant properties. In this study, we evaluated the ability of these yeast-derived recombinant avenanthramides to inhibit major hallmarks of colon cancer cells, including sustained proliferation, migration and epithelial-mesenchymal transition (EMT). Using the human colon adenocarcinoma cell line HT29, we compared the impact of YAvns and natural Avns, including Avn-A and Avn-C, on colon cancer cells by performing MTT, clonogenic, adhesion, migration, and anchorage-independent growth assays, and analyzing the expression of EMT markers. We found that both YAvns and Avns were able to inhibit colon cancer cell growth by increasing the expression of p21, p27 and p53 proteins. However, YAvns resulted more effective than natural compounds in inhibiting cancer cell migration and reverting major molecular features of the EMT process, including the down-regulation of E-cadherin mRNA and protein levels.

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Metabolic rewiring in the promotion of cancer metastasis: mechanisms and therapeutic implications

Oncogene ◽

10.1038/s41388-020-01432-7 ◽

2020 ◽

Vol 39 (39) ◽

pp. 6139-6156 ◽

Cited By ~ 3

Author(s):

Qinyao Wei ◽

Yun Qian ◽

Jun Yu ◽

Chi Chun Wong

Keyword(s):

Cancer Cells ◽

Tumor Metastasis ◽

Molecular Mechanisms ◽

Cancer Metastasis ◽

Epithelial Mesenchymal Transition ◽

Molecular Targets ◽

Mesenchymal Transition ◽

Therapeutic Implications ◽

Metastatic Cascade ◽

Metastatic Colonization

Abstract Tumor metastasis is the major cause of mortality from cancer. Metabolic rewiring and the metastatic cascade are highly intertwined, co-operating to promote multiple steps of cancer metastasis. Metabolites generated by cancer cells influence the metastatic cascade, encompassing epithelial-mesenchymal transition (EMT), survival of cancer cells in circulation, and metastatic colonization at distant sites. A variety of molecular mechanisms underlie the prometastatic effect of tumor-derived metabolites, such as epigenetic deregulation, induction of matrix metalloproteinases (MMPs), promotion of cancer stemness, and alleviation of oxidative stress. Conversely, metastatic signaling regulates expression and activity of rate-limiting metabolic enzymes to generate prometastatic metabolites thereby reinforcing the metastasis cascade. Understanding the complex interplay between metabolism and metastasis could unravel novel molecular targets, whose intervention could lead to improvements in the treatment of cancer. In this review, we summarized the recent discoveries involving metabolism and tumor metastasis, and emphasized the promising molecular targets, with an update on the development of small molecule or biologic inhibitors against these aberrant situations in cancer.

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Association of the Epithelial–Mesenchymal Transition (EMT) with Cisplatin Resistance

International Journal of Molecular Sciences ◽

10.3390/ijms21114002 ◽

2020 ◽

Vol 21 (11) ◽

pp. 4002 ◽

Cited By ~ 9

Author(s):

Milad Ashrafizadeh ◽

Ali Zarrabi ◽

Kiavash Hushmandi ◽

Mahshad Kalantari ◽

Reza Mohammadinejad ◽

...

Keyword(s):

Drug Resistance ◽

Cancer Cells ◽

Tumor Cells ◽

Epithelial Mesenchymal Transition ◽

Therapy Resistance ◽

Nuclear Factor Κb ◽

Molecular Pathways ◽

Cancer Resistance ◽

Mesenchymal Transition ◽

The Impact

Therapy resistance is a characteristic of cancer cells that significantly reduces the effectiveness of drugs. Despite the popularity of cisplatin (CP) as a chemotherapeutic agent, which is widely used in the treatment of various types of cancer, resistance of cancer cells to CP chemotherapy has been extensively observed. Among various reported mechanism(s), the epithelial–mesenchymal transition (EMT) process can significantly contribute to chemoresistance by converting the motionless epithelial cells into mobile mesenchymal cells and altering cell–cell adhesion as well as the cellular extracellular matrix, leading to invasion of tumor cells. By analyzing the impact of the different molecular pathways such as microRNAs, long non-coding RNAs, nuclear factor-κB (NF-ĸB), phosphoinositide 3-kinase-related protein kinase (PI3K)/Akt, mammalian target rapamycin (mTOR), and Wnt, which play an important role in resistance exhibited to CP therapy, we first give an introduction about the EMT mechanism and its role in drug resistance. We then focus specifically on the molecular pathways involved in drug resistance and the pharmacological strategies that can be used to mitigate this resistance. Overall, we highlight the various targeted signaling pathways that could be considered in future studies to pave the way for the inhibition of EMT-mediated resistance displayed by tumor cells in response to CP exposure.

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Histone Deacetylase Inhibitors and Phenotypical Transformation of Cancer Cells

Cancers ◽

10.3390/cancers11020148 ◽

2019 ◽

Vol 11 (2) ◽

pp. 148 ◽

Cited By ~ 20

Author(s):

Anna Wawruszak ◽

Joanna Kalafut ◽

Estera Okon ◽

Jakub Czapinski ◽

Marta Halasa ◽

...

Keyword(s):

Cancer Cells ◽

Histone Deacetylase ◽

Histone Deacetylase Inhibitors ◽

Hematological Malignancies ◽

Epithelial Mesenchymal Transition ◽

Therapeutic Potential ◽

Migration And Invasion ◽

Mesenchymal Transition ◽

Clinical Disorders ◽

The Impact

Histone deacetylase inhibitors (HDIs) are a group of potent epigenetic drugs which have been investigated for their therapeutic potential in various clinical disorders, including hematological malignancies and solid tumors. Currently, several HDIs are already in clinical use and many more are on clinical trials. HDIs have shown efficacy to inhibit initiation and progression of cancer cells. Nevertheless, both pro-invasive and anti-invasive activities of HDIs have been reported, questioning their impact in carcinogenesis. The aim of this review is to compile and discuss the most recent findings on the effect of HDIs on the epithelial-mesenchymal transition (EMT) process in human cancers. We have summarized the impact of HDIs on epithelial (E-cadherin, β-catenin) and mesenchymal (N-cadherin, vimentin) markers, EMT activators (TWIST, SNAIL, SLUG, SMAD, ZEB), as well as morphology, migration and invasion potential of cancer cells. We further discuss the use of HDIs as monotherapy or in combination with existing or novel anti-neoplastic drugs in relation to changes in EMT.

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Loss of FBP1 by aPKC-ι/Snail Pathway-Mediated Repression Promotes Invasion and Aerobic Glycolysis of Intrahepatic Cholangiocarcinoma

Frontiers in Oncology ◽

10.3389/fonc.2021.756419 ◽

2021 ◽

Vol 11 ◽

Author(s):

Meng Gao ◽

Chengjie Mei ◽

Yonghua Guo ◽

Peng Xia ◽

Hao Zhang ◽

...

Keyword(s):

Glucose Metabolism ◽

Cancer Cells ◽

Intrahepatic Cholangiocarcinoma ◽

Molecular Mechanisms ◽

Epithelial Mesenchymal Transition ◽

Aerobic Glycolysis ◽

Treatment Strategies ◽

Vital Role ◽

Mesenchymal Transition ◽

Primary Liver Tumor

Intrahepatic cholangiocarcinoma (ICC) is one of the most commonly diagnosed malignancies worldwide, and the second most common primary liver tumor. The lack of effective diagnostic and treatment methods results in poor patient prognosis and high mortality rate. Atypical protein kinase C-ι (aPKC-ι) is highly expressed in primary and metastatic ICC tissues, and regulates epithelial mesenchymal transition (EMT) through the aPKC-ι/P-Sp1/Snail signaling pathway. Recent studies have correlated aberrant glucose metabolism with EMT. Given the vital role of FBP1 in regulating glucose metabolism in cancer cells, we hypothesized that aPKC-ι downregulates FBP1 in ICC cells through the Snai1 pathway, and enhances glycolysis and metastasis. We confirmed the ability of aPKC-ι promotes glycolysis, invasion and metastasis of cancer cells, and further demonstrated that FBP1 inhibits the malignant properties of ICC cells by antagonizing aPKC-ι. Our findings provide novel insights into the molecular mechanisms of ICC progression and metastasis, as well as a theoretical basis for exploring new treatment strategies.

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