Medicine and Health Sciences Commons^™

Epigenetic Regulation And Post-Translational Modifications Of Snai1 In Cancer Metastasis, Bo Dong, Yadi Wu

Pharmacology and Nutritional Sciences Faculty Publications

SNAI1, a zinc finger transcription factor, not only acts as the master regulator of epithelialmesenchymal transition (EMT) but also functions as a driver of cancer progression, including cell invasion, survival, immune regulation, stem cell properties, and metabolic regulation. The regulation of SNAI1 occurs at the transcriptional, translational, and predominant post-translational levels including phosphorylation, acetylation, and ubiquitination. Here, we discuss the regulation and role of SNAI1 in cancer metastasis, with a particular emphasis on epigenetic regulation and posttranslational modifications. Understanding how signaling networks integrate with SNAI1 in cancer progression will shed new light on the mechanism of tumor metastasis and help …

Tackle Epithelial-Mesenchymal Transition With Epigenetic Drugs In Cancer, Bo Dong, Zhaoping Qiu, Yadi Wu

Pharmacology and Nutritional Sciences Faculty Publications

Epithelial-mesenchymal Transition (EMT) is a de-differentiation process in which epithelial cells lose their epithelial properties to acquire mesenchymal features. EMT is essential for embryogenesis and wound healing but is aberrantly activated in pathological conditions like fibrosis and cancer. Tumor-associated EMT contributes to cancer cell initiation, invasion, metastasis, drug resistance and recurrence. This dynamic and reversible event is governed by EMT-transcription factors (EMT-TFs) with epigenetic complexes. In this review, we discuss recent advances regarding the mechanisms that modulate EMT in the context of epigenetic regulation, with emphasis on epigenetic drugs, such as DNA demethylating reagents, inhibitors of histone modifiers and non-coding …

Alcohol And Cancer Stem Cells, Mei Xu, Jia Luo

Pharmacology and Nutritional Sciences Faculty Publications

Heavy alcohol consumption has been associated with increased risk of several cancers, including cancer of the colon, rectum, female breast, oral cavity, pharynx, larynx, liver, and esophagus. It appears that alcohol exposure not only promotes carcinogenesis but also enhances the progression and aggressiveness of existing cancers. The molecular mechanisms underlying alcohol tumor promotion, however, remain unclear. Cancer stem cells (CSC), a subpopulation of cancer cells with self-renewal and differentiation capacity, play an important role in tumor initiation, progression, metastasis, recurrence, and therapy resistance. The recent research evidence suggests that alcohol increases the CSC population in cancers, which may underlie alcohol-induced …

Dub3 Inhibition Suppresses Breast Cancer Invasion And Metastasis By Promoting Snail1 Degradation, Yadi Wu, Yu Wang, Yiwei Lin, Yajuan Liu, Yifan Wang, Jianhang Jia, Puja Singh, Young-In Chi, Chi Wang, Chenfang Dong, Wei Li, Min Tao, Dana L. Napier, Qiuying Shi, Jiong Deng, B. Mark Evers, Binhua P. Zhou

Pharmacology and Nutritional Sciences Faculty Publications

Snail1, a key transcription factor of epithelial–mesenchymal transition (EMT), is subjected to ubiquitination and degradation, but the mechanism by which Snail1 is stabilized in tumours remains unclear. We identify Dub3 as a bona fide Snail1 deubiquitinase, which interacts with and stabilizes Snail1. Dub3 is overexpressed in breast cancer; knockdown of Dub3 resulted in Snail1 destabilization, suppressed EMT and decreased tumour cell migration, invasion, and metastasis. These effects are rescued by ectopic Snail1 expression. IL-6 also stabilizes Snail1 by inducing Dub3 expression, the specific inhibitor WP1130 binds to Dub3 and inhibits the Dub3-mediating Snail1 stabilization in vitroand in vivo. …

Erbb2 And P38Γ Mapk Mediate Alcohol-Induced Increase In Breast Cancer Stem Cells And Metastasis, Mei Xu, Zhenhua Ren, Xin Wang, Ashley Comer, Jacqueline A. Frank, Zun-Ji Ke, Yi Huang, Zhuo Zhang, Xianglin Shi, Siying Wang, Jia Luo

Pharmacology and Nutritional Sciences Faculty Publications

Background: Both epidemiological and experimental studies suggest that excessive alcohol exposure increases the risk for breast cancer and enhances metastasis/recurrence. We have previously demonstrated that alcohol enhanced the migration/invasion of breast cancer cells and cancer cells overexpressing ErbB2/HER2 were more sensitive to alcohol exposure. However, the underlying mechanisms remain unclear. This study was designed to investigate the mechanisms underlying alcohol-enhanced aggressiveness of breast cancer. Cancer stem cells (CSCs) play a critical role in cancer metastasis and recurrence.

Methods: We evaluated the effect of chronic alcohol exposure on mammary tumor development/metastasis in MMTV-neu transgenic mice and investigated the cell signaling in …

Chronic Ethanol Exposure Enhances The Aggressiveness Of Breast Cancer: The Role Of P38Γ, Mei Xu, Siying Wang, Zhenhua Ren, Jacqueline A. Frank, Xiuwei H. Yang, Zhuo Zhang, Zun-Ji Ke, Xianglin Shi, Jia Luo

Pharmacology and Nutritional Sciences Faculty Publications

Both epidemiological and experimental studies suggest that ethanol may enhance aggressiveness of breast cancer. We have previously demonstrated that short term exposure to ethanol (12–48 hours) increased migration/invasion in breast cancer cells overexpressing ErbB2, but not in breast cancer cells with low expression of ErbB2, such as MCF7, BT20 and T47D breast cancer cells. In this study, we showed that chronic ethanol exposure transformed breast cancer cells that were not responsive to short term ethanol treatment to a more aggressive phenotype. Chronic ethanol exposure (10 days - 2 months) at 100 (22 mM) or 200 mg/dl (44 mM) caused the …

Activation Of The Nf-Κb Pathway As A Mechanism Of Alcohol Enhanced Progression And Metastasis Of Human Hepatocellular Carcinoma, Fei Wang, Jin-Lian Yang, Ke-Ke Yu, Mei Xu, You-Zhi Xu, Li Chen, Yan-Min Lu, Hao-Shu Fang, Xin-Yi Wang, Zhong-Qian Hu, Fei-Fei Li, Lixin Kan, Jia Luo, Si-Ying Wang

Pharmacology and Nutritional Sciences Faculty Publications

BACKGROUND: Hepatocellular carcinoma (HCC), the most common form of primary liver cancer, is the third leading cause of cancer-related death in human. Alcohol is a known risk factor for HCC. However it is still unclear whether and how alcohol enhances the progression and metastasis of existing HCC.

METHODS AND RESULTS: We first retrospectively investigated 52 HCC patients (24 alcohol-drinkers and 28 non-drinkers), and found a positive correlation between alcohol consumption and advanced Tumor-Node-Metastasis (TNM) stages, higher vessel invasion and poorer prognosis. In vitro and in vivo experiments further indicated that alcohol promoted the progression and migration/invasion of HCC. Specifically, in …