Beyond a tumor suppressor: Soluble <scp>E</scp>‐cadherin promotes the progression of cancer

Hu, Qi-Ping; Kuang, Jing‐Ya; Yang, Qingkai; Bian, Xiu‐Wu; Yu, Shanshan

doi:10.1002/ijc.29982

Cited by 100 publications

(113 citation statements)

References 90 publications

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“…3C and SI Appendix, Fig. S4A) and notably, 6 of these genes (ARNTL, CEACAM7, GATA2, HHEX, KLRG1, and OGN) have been reported to possess tumor suppressor activity (18)(19)(20)(21)(22)(23). qPCR analysis of the 10 genes in three additional breast cancer cell lines revealed that their expression was down-regulated in hypoxia in a similar manner to that observed in MCF7 breast cancer cells (SI Appendix, Fig.…”

Section: Resultsmentioning

confidence: 59%

G9a drives hypoxia-mediated gene repression for breast cancer cell survival and tumorigenesis

Casciello

Al-Ejeh

Kelly

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

110

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G9a is an epigenetic regulator that methylates H3K9, generally causing repression of gene expression, and participates in diverse cellular functions. G9a is genetically deregulated in a variety of tumor types and can silence tumor suppressor genes and, therefore, is important for carcinogenesis. Although hypoxia is recognized to be an adverse factor in tumor growth and metastasis, the role of G9a in regulating gene expression in hypoxia has not been described extensively. Here, we show that G9a protein stability is increased in hypoxia via reduced proline hydroxylation and, hence, inefficient degradation by the proteasome. This inefficiency leads to an increase in H3K9me2 at its target promoters. Blocking the methyltransferase activity of G9a inhibited cellular proliferation and migration in vitro and tumor growth in vivo. Furthermore, an increased level of G9a is a crucial factor in mediating the hypoxic response by down-regulating the expression of specific genes, including ARNTL, CEACAM7, GATA2, HHEX, KLRG1, and OGN. This down-regulation can be rescued by a small molecule inhibitor of G9a. Based on the hypothesis that the changes in gene expression would influence patient outcomes, we have developed a prognostic G9a-suppressed gene signature that can stratify breast cancer patients. Together, our findings provide an insight into the role G9a plays as an epigenetic mediator of hypoxic response, which can be used as a diagnostic marker, and proposes G9a as a therapeutic target for solid cancers.

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Section: Resultsmentioning

confidence: 59%

G9a drives hypoxia-mediated gene repression for breast cancer cell survival and tumorigenesis

Casciello

Al-Ejeh

Kelly

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

110

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“…On the other hand, (i) ACTA2 which has been related to increased cell motility in breast cancer and other cancer types (50, 51), (ii) POSTN , a protein secreted by cancer cells that has been described to facilitate cell motility and was recently purposed as an interesting target for prevention and treatment of breast tumor metastasis (52, 53), and (iii) VCAN , known to enhance tumorigenesis and cell mobility, invasion, and survival of breast tumors (54), are all dramatically silenced in IF1-overexpressing breast cancer cells. Besides, we found that IF1 overexpression increased the presence of the epithelial marker E-cadherin involved in maintenance of cell and epithelial tissue integrity and inversely correlated with invasion and metastasis (55, 56). Furthermore, integrin β1 an adhesion molecule (55) related to migration, extravasation, and metastasis (44) is found significantly reduced in IF1-cells.…”

Section: Discussionmentioning

confidence: 79%

Overexpression of the ATPase Inhibitory Factor 1 Favors a Non-metastatic Phenotype in Breast Cancer

et al. 2017

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Partial suppression of mitochondrial oxidative phosphorylation and the concurrent activation of aerobic glycolysis is a hallmark of proliferating cancer cells. Overexpression of the ATPase inhibitory factor 1 (IF1), an in vivo inhibitor of the mitochondrial ATP synthase, is observed in most prevalent human carcinomas favoring metabolic rewiring to an enhanced glycolysis and cancer progression. Consistently, a high expression of IF1 in hepatocarcinomas and in carcinomas of the lung, bladder, and stomach and in gliomas is a biomarker of bad patient prognosis. In contrast to these findings, we have previously reported that a high expression level of IF1 in breast carcinomas is indicative of less chance to develop metastatic disease. This finding is especially relevant in the bad prognosis group of patients bearing triple-negative breast carcinomas. To investigate the molecular mechanisms that underlie the differential behavior of IF1 in breast cancer progression, we have developed the triple-negative BT549 breast cancer cell line that overexpresses IF1 stably. When compared to controls, IF1-cells partially shut down respiration and enhance aerobic glycolysis. Transcriptomic analysis suggested that migration and invasion were specifically inhibited in IF1-overexpressing breast cancer cells. Analysis of gene expression by qPCR and western blotting indicate that IF1 overexpression supports the maintenance of components of the extracellular matrix (ECM) and E-cadherin concurrently with the downregulation of components and signaling pathways involved in epithelial to mesenchymal transition. The overexpression of IF1 in breast cancer cells has no effect in the rates of cellular proliferation and in the cell death response to staurosporine and hydrogen peroxide. However, the overexpression of IF1 significantly diminishes the ability of the cells to grow in soft agar and to migrate and invade when compared to control cells. Overall, the results indicate that IF1 overexpression despite favoring a metabolic phenotype prone to cancer progression in the specific case of breast cancer cells also promotes the maintenance of the ECM impeding metastatic disease. These findings hence provide a mechanistic explanation to the better prognosis of breast cancer patients bearing tumors with high expression level of IF1.

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“…15, 22 The study presented here identifies a gene signature composed of the TGFβ signaling pathway and EMT genes under the control of CdGAP in ErbB2-expressing breast cancer cells. We demonstrate that CdGAP acts as a novel co-transcriptional repressor with Zeb2 to suppress E-cadherin expression in breast cancer cells.…”

Section: Discussionmentioning

confidence: 99%

The Cdc42/Rac1 regulator CdGAP is a novel E-cadherin transcriptional co-repressor with Zeb2 in breast cancer

Northey

Pelletier

et al. 2017

Oncogene

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The loss of E-cadherin causes dysfunction of the cell-cell junction machinery, which is an initial step in epithelial-to-mesenchymal transition (EMT), facilitating cancer cell invasion and the formation of metastases. A set of transcriptional repressors of E-cadherin (CDH1) gene expression, including Snail1, Snail2 and Zeb2 mediate E-cadherin down-regulation in breast cancer. However, the molecular mechanisms underlying the control of E-cadherin expression in breast cancer progression remain largely unknown. Here, by using global gene expression approaches, we uncover a novel function for Cdc42 GTPase-activating protein (CdGAP) in the regulation of expression of genes involved in EMT. We found that CdGAP used its proline-rich domain to form a functional complex with Zeb2 to mediate the repression of E-cadherin expression in ErbB2-transformed breast cancer cells. Conversely, knockdown of CdGAP expression led to a decrease of the transcriptional repressors Snail1 and Zeb2, and this correlated with an increase in E-cadherin levels, restoration of cell-cell junctions, and epithelial-like morphological changes. In vivo, loss of CdGAP in ErbB2-transformed breast cancer cells impaired tumor growth and suppressed metastasis to lungs. Finally, CdGAP was highly expressed in basal-type breast cancer cells, and its strong expression correlated with poor prognosis in breast cancer patients. Together, these data support a previously unknown nuclear function for CdGAP where it cooperates in a GAP-independent manner with transcriptional repressors to function as a critical modulator of breast cancer through repression of E-cadherin transcription. Targeting Zeb2-CdGAP interactions may represent novel therapeutic opportunities for breast cancer treatment.

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Beyond a tumor suppressor: Soluble E‐cadherin promotes the progression of cancer

Cited by 100 publications

References 90 publications

G9a drives hypoxia-mediated gene repression for breast cancer cell survival and tumorigenesis

G9a drives hypoxia-mediated gene repression for breast cancer cell survival and tumorigenesis

Overexpression of the ATPase Inhibitory Factor 1 Favors a Non-metastatic Phenotype in Breast Cancer

The Cdc42/Rac1 regulator CdGAP is a novel E-cadherin transcriptional co-repressor with Zeb2 in breast cancer

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