E3 ubiquitin protein ligase, E6-associated protein (E6-AP) regulates PI3K-Akt signaling and prostate cell growth

Metastatic disease is the major cause of breast cancer-related death and despite many advances, current therapies are rarely curative. Tumor cell migration and invasion require actin cytoskeletal reorganization to endow cells with capacity to disseminate and initiate the formation of secondary tumors. However, it is still unclear how these migratory cells colonize distant tissues to form macrometastases. The E6-associated protein, E6AP, acts both as an E3 ubiquitin-protein ligase and as a coactivator of steroid hormone receptors. We report that E6AP suppresses breast cancer invasiveness, colonization, and metastasis in mice, and in breast cancer patients, loss of E6AP associates with poor prognosis, particularly for basal breast cancer. E6AP regulates actin cytoskeletal remodeling via regulation of Rho GTPases, acting as a negative regulator of ECT2, a GEF required for activation of Rho GTPases. E6AP promotes ubiquitination and proteasomal degradation of ECT2 for which high expression predicts poor prognosis in breast cancer patients. We conclude that E6AP suppresses breast cancer metastasis by regulating actin cytoskeleton remodeling through the control of ECT2 and Rho GTPase activity. These findings establish E6AP as a novel suppressor of metastasis and provide a compelling rationale for inhibition of ECT2 as a therapeutic approach for patients with metastatic breast cancer.Cancer Res; 76(14); 4236-48. Ó2016 AACR.

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“…E6AP is an E3-ligase that regulates the transcript and protein levels of the steroid hormone receptors (42)(43)(44)(45).…”

Section: Discussionmentioning

confidence: 99%

The E3-ligase E6AP Represses Breast Cancer Metastasis via Regulation of ECT2-Rho Signaling

et al. 2016

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“…Although most of prostate cancer patients are treated with androgen depletion strategies due to androgen‐dependent progression of prostate cancer, many patients have a relapse with androgen‐independent prostate cancer or exhibit chemoresistance (Feldman & Feldman, ). One reason for development of androgen‐independent prostate cancer therapies is to avoid excessive activation of AKT proteins through mutations of phosphatase and tensin homolog (PTEN) and/or hyper‐activation of PI3K (Kumar et al, ; Srinivasan & Nawaz, ). Therefore, inhibiting the PI3K/AKT signal transduction pathway is an important therapeutic approach for treatment of prostate cancer.…”

Section: Discussionmentioning

confidence: 99%

Chrysin induces death of prostate cancer cells by inducing ROS and ER stress

Ryu

Lim

Bazer

et al. 2017

Journal Cellular Physiology

115

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Chrysin is a natural flavone found in numerous plant extracts, honey, and propolis that has multiple biological activities including anti-cancer effects. Understanding of biological mechanisms mediated in response to chrysin in cancerous cells may provide novel insight into chemotherapeutic approaches with reduced side effects in cancers. In the present study, we investigated functional roles of chrysin in progression of prostate cancer cells using DU145 and PC-3 cell lines. The results showed that chrysin induced apoptosis of cells evidenced by DNA fragmentation and increasing the population of both DU145 and PC-3 cells in the sub-G phase of the cell cycle. In addition, chrysin reduced expression of proliferating cell nuclear antigen in the prostate cancer cell lines compared to untreated prostate cancer cells. Moreover, chrysin induced loss of mitochondria membrane potential (MMP), while increasing production of reactive oxygen species (ROS) and lipid peroxidation in a dose-dependent manner. Also, it induced endoplasmic reticulum (ER) stress through activation of unfolded protein response (UPR) proteins including PRKR-like ER kinase (PERK), eukaryotic translation initiation factor 2α (eIF2α), and 78 kDa glucose-regulated protein (GRP78) in DU145 and PC-3 cells. The chrysin-mediated intracellular signaling pathways suppressed phosphoinositide 3-kinase (PI3K) and the abundance of AKT, P70S6K, S6, and P90RSK proteins, but stimulated mitogen-activated protein kinases (MAPK) and activation of ERK1/2 and P38 proteins in the prostate cancer cells. Collectively, these results indicate that chrysin initiates cell death through induction of mitochondrial-mediated apoptosis and ER stress, and regulation of signaling pathways responsible for proliferation of prostate cancer cells.

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“…In addition, it has been reported that UBE3A can promote proliferation and inhibit apoptosis of cervical cancer cells (4). In prostate cancer cells, UBE3A has been shown to regulate the phosphoinositide 3-kinase-Akt pathway, which results in increased prostate cell growth, proliferation and decreased apoptosis (24). Therefore, it was hypothesized that in breast cancer cells, UBE3A may affect cell signaling pathways and influence cell biological behavior.…”

Section: Discussionmentioning

confidence: 99%

Knockdown of ubiquitin protein ligase E3A affects proliferation and invasion, and induces apoptosis of breast cancer cells through regulation of annexin A2

Zhou

Deng

Liu

et al. 2012

Molecular Medicine Reports

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The present study used RNA interference (RNAi) to study how the expression of annexin A2 was affected by ubiquitin protein ligase E3A (UBE3A). In addition, the proliferation, apoptosis and invasiveness of BT-549 breast cancer cells was studied following knockdown of UBE3A. Three pairs of small interfering RNA (siRNA) fragments targeting UBE3A were designed and transfected into the BT-549 cells. The effects of silencing UBE3A were detected by reverse transcription-polymerase chain reaction and western blotting, and the same methods were used to detect the expression levels of annexin A2. Cell proliferation was determined using the Cell Counting kit-8, and flow cytometry and a Transwell chamber assay were used to assess the rate of cell apoptosis and invasion, respectively. Following transfection with the three siRNAs targeting UBE3A for 72 h, the mRNA expression levels of UBE3A were downregulated, as compared with those in the untreated groups, and siRNA1 was the shown to be the most effective siRNA for silencing UBE3A expression. The protein expression levels were concordant with the mRNA expression levels of UBE3A. In addition, the mRNA and protein expression levels of annexin A2 were downregulated. Cellular proliferation and invasion of the siRNA1 group was inhibited as compared with those in the untreated groups, and apoptosis of UBE3A-siRNA1 cells was increased as compared with that in the untreated groups. The results of the present study indicated that UBE3A may regulate the expression of annexin A2, resulting in promotion of proliferation and invasion and suppression of apoptosis in BT-549 cells.

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E3 ubiquitin protein ligase, E6-associated protein (E6-AP) regulates PI3K-Akt signaling and prostate cell growth

Cited by 28 publications

References 24 publications

The E3-ligase E6AP Represses Breast Cancer Metastasis via Regulation of ECT2-Rho Signaling

The E3-ligase E6AP Represses Breast Cancer Metastasis via Regulation of ECT2-Rho Signaling

Chrysin induces death of prostate cancer cells by inducing ROS and ER stress

Knockdown of ubiquitin protein ligase E3A affects proliferation and invasion, and induces apoptosis of breast cancer cells through regulation of annexin A2

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