SLUG is a direct transcriptional repressor of PTEN tumor suppressor

Uygur, Berna; Abramo, Katrina; Leikina, Evgenia; Vary, Calvin P.H.; Liaw, Lucy; Wu, Wen Shu

doi:10.1002/pros.22974

Cited by 34 publications

(27 citation statements)

References 30 publications

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“…However, the adverse effects of PI3K/Akt inhibitors restrict their clinical application [19]. In prostate cancer, PI3K/Akt signaling pathway could be activated by slug because slug is a direct transcriptional repressor of PTEN tumor suppressor [21]. In the present study, slug did not alter PTEN expression in HCC cells (data not shown).…”

Section: Discussionmentioning

confidence: 47%

WITHDRAWN: Positive feedback between slug and Akt promotes hepatocellular carcinoma growth via CDK6 expression

Lu¹,

Zhang²,

Yin³

et al. 2020

Preprint

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Background Hepatocellular carcinoma (HCC) is a rapidly growing tumor associated with a propensity for vascular invasion and metastasis, but the mechanism of HCC growth is not fully understood. The objective of this study is to investigate the role of the transcriptional repressor slug in HCC growth and its detailed mechanism. Methods Lentivirus-mediated slug overexpression as well as CRISPR/Cas9-mediated slug knockout were conducted in hepatic or HCC cells. Then cell growth was evaluated in culture dishes as well as nude mice xenografts. Transcriptome analysis was used to explore the detailed mechanism of slug-induced HCC growth. Results Slug significantly facilitated HCC growth in vitro and in vivo. Mechanism dissection via transcriptome analysis revealed that slug transcriptionally upregulated PIK3CD and PIK3R3 expression and then activated the Akt/CDK6 signaling pathway. Administration of either the PI3K/Akt signaling inhibitor MK2206 or the CDK4/6 inhibitor PD-0332991 abrogated slug-induced HCC growth. In addition, administration of MK2206 also suppressed slug expression in HCC cells. Immunohistochemistry staining indicated that Akt activity and CDK6 expression were significantly associated with slug expression in human HCC tissues. Conclusions Our study determined the promoting role of slug in HCC growth and revealed that the positive feedback between slug and Akt conferred HCC growth via CDK6 expression. The CDK4/6 inhibitor PD-0332991 might be a promising drug for slug/Akt-induced HCC growth.

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Section: Discussionmentioning

confidence: 47%

WITHDRAWN: Positive feedback between slug and Akt promotes hepatocellular carcinoma growth via CDK6 expression

Lu¹,

Zhang²,

Yin³

et al. 2020

Preprint

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“…Positive transcriptional regulators of PTEN gene expression, including p53, early growth response transcriptional factor 1 (EGR1), activating transcription factor 2, and peroxisome proliferator-activated receptor γ (PPARγ), directly bind to the PTEN promoter ( 78 – 80 ). Negative regulators of PTEN gene expression, including SNAIL and SLUG, compete with p53 to occupy the PTEN promoter ( 81 , 82 ). PTEN transcription is also negatively regulated by the polycomb complex protein BMI1, c-repeat binding factor 1 (CBF1), c-Jun, and NF-κB ( 83 – 85 ).…”

Section: Aberrant Homeostatic Regulation Of Pten In Tumorigenesismentioning

confidence: 99%

Role of Ubiquitination in PTEN Cellular Homeostasis and Its Implications in GB Drug Resistance

et al. 2020

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Glioblastoma (GB) is the most common and aggressive brain malignancy, characterized by heterogeneity and drug resistance. PTEN, a crucial tumor suppressor, exhibits phosphatase-dependent (PI3K-AKT-mTOR pathway)/independent (nucleus stability) activities to maintain the homeostatic regulation of numerous physiological processes. Premature and absolute loss of PTEN activity usually tends to cellular senescence. However, monoallelic loss of PTEN is frequently observed at tumor inception, and absolute loss of PTEN activity also occurs at the late stage of gliomagenesis. Consequently, aberrant PTEN homeostasis, mainly regulated at the post-translational level, renders cells susceptible to tumorigenesis and drug resistance. Ubiquitination-mediated degradation or deregulated intracellular localization of PTEN hijacks cell growth rheostat control for neoplastic remodeling. Functional inactivation of PTEN mediated by the overexpression of ubiquitin ligases (E3s) renders GB cells adaptive to PTEN loss, which confers resistance to EGFR tyrosine kinase inhibitors and immunotherapies. In this review, we discuss how glioma cells develop oncogenic addiction to the E3s-PTEN axis, promoting their growth and proliferation. Antitumor strategies involving PTEN-targeting E3 ligase inhibitors can restore the tumor-suppressive environment. E3 inhibitors collectively reactivate PTEN and may represent next-generation treatment against deadly malignancies such as GB.

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“…These changes in protein expression in cancer cells may directly contribute to their increased aggressiveness. For instance, the EMT marker Slug plays a major role in prostate cancer progression through regulation of proliferation and promotes pAKT activity via suppression of PTEN (50). Increased Slug expression could initiate EMT in the prostate cancer-muscle microenvironment.…”

Section: Muscle Cell-induced Progression Of Prostate Cancer Cellsmentioning

confidence: 99%

Interactions with Muscle Cells Boost Fusion, Stemness, and Drug Resistance of Prostate Cancer Cells

Uygur

Leikina

Melikov

et al. 2019

Molecular Cancer Research

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Poorly understood interactions with nonmalignant cells within the tumor microenvironment play an important role in cancer progression. Here, we explored interactions between prostate cancer and muscle cells that surround the prostate. We found that coculturing of prostate cancer cells with skeletal or smooth muscle cells expands the subpopulations of cancer cells with features characteristic of cancer stem-like cells, including anchorage-independent growth, elevated CD133 expression, and drug resistance. These changes in the properties of cancer cells depend on: (i) the muscle cell-induced increases in the concentrations of interleukins 4 and 13; (ii) the cytokine-induced upregula-tion of the expression of syncytin 1 and annexin A5; and (iii) cancer cell fusion. In human prostate cancer tissues, expression of syncytin 1 and annexin A5, proteins that we found to be required for the cell fusion, positively correlated with the cancer development suggesting that these proteins can be used as biomarkers to evaluate cancer progression and potential therapeutic targets. Implications:The discovered effects of muscle cells on prostate cancer cells reveal a novel and specific pathway by which muscle cells in the microenvironment of prostate cancer cells promote cell fusion and cancer progression.

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SLUG is a direct transcriptional repressor of PTEN tumor suppressor

Cited by 34 publications

References 30 publications

WITHDRAWN: Positive feedback between slug and Akt promotes hepatocellular carcinoma growth via CDK6 expression

WITHDRAWN: Positive feedback between slug and Akt promotes hepatocellular carcinoma growth via CDK6 expression

Role of Ubiquitination in PTEN Cellular Homeostasis and Its Implications in GB Drug Resistance

Interactions with Muscle Cells Boost Fusion, Stemness, and Drug Resistance of Prostate Cancer Cells

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