Epidermal Growth Factor Promotes Protein Degradation of Epithelial Protein Lost in Neoplasm (EPLIN), a Putative Metastasis Suppressor, during Epithelial-mesenchymal Transition

Zhang, Shumin; Wang, Xu; Iqbal, Shareen; Wang, Yanru; Osunkoya, Adeboye O.; Chen, Zhuo; Shin, Dong M.; Hu, Yuan; Wang, Yongqiang A.; Zhau, Haiyen E.; Chung, Leland W.K.; Ritenour, Chad W.M.; Küçük, Ömer; Wu, Daqing

doi:10.1074/jbc.m112.438341

Cited by 40 publications

(39 citation statements)

References 48 publications

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“…S2R and S in the supplemental material), such as the interferon pathway (57)(58)(59), the tumor necrosis factor (TNF) pathway (60), and growth factors such as the EGF pathway (61). Thus, PMA induction of the PKCs operates via key inflammatory processes previously shown to induce EMT (62)(63)(64)(65) and cooperates with the TGF-␤ pathway.…”

Section: Resultsmentioning

confidence: 99%

Chromatinized Protein Kinase C-θ Directly Regulates Inducible Genes in Epithelial to Mesenchymal Transition and Breast Cancer Stem Cells

Zafar

Hardy

et al. 2014

Molecular and Cellular Biology

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g Epithelial to mesenchymal transition (EMT) is activated during cancer invasion and metastasis, enriches for cancer stem cells (CSCs), and contributes to therapeutic resistance and disease recurrence. Signal transduction kinases play a pivotal role as chromatin-anchored proteins in eukaryotes. Here we report for the first time that protein kinase C-theta (PKC-) promotes EMT by acting as a critical chromatin-anchored switch for inducible genes via transforming growth factor ␤ (TGF-␤) and the key inflammatory regulatory protein NF-B. Chromatinized PKC-exists as an active transcription complex and is required to establish a permissive chromatin state at signature EMT genes. Genome-wide analysis identifies a unique cohort of inducible PKC--sensitive genes that are directly tethered to PKC-in the mesenchymal state. Collectively, we show that cross talk between signaling kinases and chromatin is critical for eliciting inducible transcriptional programs that drive mesenchymal differentiation and CSC formation, providing novel mechanisms to target using epigenetic therapy in breast cancer. Epithelial to mesenchymal transition (EMT) is a key step in cancer progression and the process of metastasis that creates a reservoir for cancer stem cells (CSCs) and is associated with highly aggressive traits (1-4). As well as driving metastasis, these CSCs, or "precursor" metastatic cells, play a pivotal role in therapeutic resistance and relapse in breast cancer patients (5, 6). Breast CSCs are a distinct subpopulation of mesenchymal cells that possess several important features, namely, expression of key surface markers (CD44 high and CD24 low ) (7), a distinct transcriptome (3), the ability to form spherical colonies in suspension cultures (termed mammospheres) (8), and enhanced resistance to chemotherapy (9, 10) and ionizing radiation (11)(12)(13)(14).Eukaryotes utilize the chromatin landscape as its epigenetic template within the nucleus of living cells in order to promote inducible gene transcription in response to environmental signals. Highly compacted chromatin structures are enriched in nucleosomes and are transcriptionally silent, and a net loss of nucleosomes from gene-specific regulatory regions increases chromatin accessibility and initiates context-specific transcriptional programs. In addition to ATP-dependent chromatin remodeling and exchange of histone variants with canonical histones, histone modifications are thought to alter gene expression, by changing chromatin structure and/or by providing a platform that promotes binding of transcriptional regulators (15-23).Novel classes of chromatin-associated enzymes that play critical roles in modulating chromatin structure within the human genome have recently been discovered. In particular, signaling kinases can act as chromatin regulators of inducible gene transcription in both higher and lower eukaryotes by two distinct mechanisms: relaying signals from the cytoplasm to the nucleus and direct association with chromatin-bound transcription complexes at activated tar...

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Section: Resultsmentioning

confidence: 99%

Chromatinized Protein Kinase C-θ Directly Regulates Inducible Genes in Epithelial to Mesenchymal Transition and Breast Cancer Stem Cells

Zafar

Hardy

et al. 2014

Molecular and Cellular Biology

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“…These results suggested that the HCC with multiple observed lesions had more serious problems in protein degradation disorder. Although, the disturbance of protein degradation has been reported to be closely associated with different cancer types [40][41][42][43], the underlying mechanisms of the disturbance of UBC signaling pathway, which only occurred in HCC with multiple observed lesions, are not clear and need further investigation. On the other hand, the ERK signaling pathway is only enriched in the HCC with a single lesion, but it is normally regulated in HCC with multiple lesions; ERK signals were well known as an extremely important regulator of cell growth and proliferation.…”

Section: Ipa Network Analysis Of the Differentially Expressed Proteinsmentioning

confidence: 93%

Comparative analysis of primary hepatocellular carcinoma with single and multiple lesions by iTRAQ-based quantitative proteomics

Xing

Huang

Wang

et al. 2015

Journal of Proteomics

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“…EGF induced EMT was found to be mainly dependent on Akt activation, as inhibition of Akt signaling abolished EGF driven EMT in PCa cell lines [62, 63]. In addition, EGF was shown to selectively induce the protein degradation of epithelial origins in neoplasm; or LIM domain and actin binding 1, LIMA-1 (EPLIN), a putative suppressor of EMT in PCa [64]. Further mechanistic analysis revealed that EGF activated the phosphorylation, ubiquitination, and degradation of EPLIN through an extracellular signal-regulated kinase 1/2 (ERK1/2)-dependent signaling cascade.…”

Section: Molecular Mechanisms Of Emt Induction In Pcamentioning

confidence: 99%

Role of Epithelial Mesenchymal Transition in Prostate Tumorigenesis

Khan¹,

Hamid²,

Adhami³

et al. 2015

CPD

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Globally, the cancer associated deaths are generally attributed to the spread of cancerous cells or their features to the nearby or distant secondary organs by a process known as metastasis. Among other factors, the metastatic dissemination of cancer cells is attributed to the reactivation of an evolutionary conserved developmental program known as epithelial to mesenchymal transition (EMT). During EMT, fully differentiated epithelial cells undergo a series of dramatic changes in their morphology, along with loss of cell to cell contact and matrix remodeling into less differentiated and invasive mesenchymal cells. Many studies provide evidence for the existence of EMT like states in prostate cancer (PCa) and suggest its possible involvement in PCa progression and metastasis. At the same time, the lack of conclusive evidence regarding the presence of full EMT in human PCa samples has somewhat dampened the interest in the field. However, ongoing EMT research provides new perspectives and unveils the enormous potential of this field in tailoring new therapeutic regimens for PCa management. This review summarizes the role of many transcription factors and other molecules that drive EMT during prostate tumorigenesis.

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Epidermal Growth Factor Promotes Protein Degradation of Epithelial Protein Lost in Neoplasm (EPLIN), a Putative Metastasis Suppressor, during Epithelial-mesenchymal Transition

Cited by 40 publications

References 48 publications

Chromatinized Protein Kinase C-θ Directly Regulates Inducible Genes in Epithelial to Mesenchymal Transition and Breast Cancer Stem Cells

Chromatinized Protein Kinase C-θ Directly Regulates Inducible Genes in Epithelial to Mesenchymal Transition and Breast Cancer Stem Cells

Comparative analysis of primary hepatocellular carcinoma with single and multiple lesions by iTRAQ-based quantitative proteomics

Role of Epithelial Mesenchymal Transition in Prostate Tumorigenesis

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