Abstract
Epithelial-to-mesenchymal transition (EMT) is one of the important underlying molecular mechanisms for most types of cancers including bladder cancer. The precise underlying molecular mechanism in EMT-mediated bladder cancer progression is far from completed. LSD1, a histone lysine-specific demethylase, is known to promote cancer cell proliferation, metastasis, and chemoresistance. We found in this study that LSD1 is highly upregulated in bladder cancer specimens, especially those underwent chemotherapy, and the elevated levels of LSD1 are highly associated with bladder cancer grades, metastasis status, and prognosis. Inhibiting or knockdown LSD1 repressed not only EMT process but also cancer progression. Mechanistically, LSD1 complexes with β-catenin to transcriptionally upregulate LEF1 and subsequently enhances EMT-mediated cancer progression. More importantly, LSD1 specific inhibitor GSK2879552 is capable of repressing tumor progression in patient-derived tumor xenograft. These findings altogether suggest that LSD1 can serve as not only a prognostic biomarker but also a promising therapeutic target in bladder cancer treatment.
Highlights
Bladder cancer (BCa) is one of the most frequently diagnosed cancers worldwide with about 429,800 new cases and 165,100 deaths annually [1]
When cells were injected into the flanks of nude mice to form xenograft tumors, the weight and size of xenografts derived from T24 with or without Lysine-specific demethylase 1 (LSD1) knockdown demonstrated the indispensability of LSD1 in BCa (Supplementary Figures S1C–E)
We found in this research that LSD1 is capable of enhancing Epithelial-to-mesenchymal transition (EMT) process and BCa cancer progression by complexing with β-catenin to transcriptionally upregulate LEF1 (Figure 5K)
Summary
Bladder cancer (BCa) is one of the most frequently diagnosed cancers worldwide with about 429,800 new cases and 165,100 deaths annually [1]. Epithelial-mesenchymal transition (EMT) plays an important role in recurrence, chemoresistance, and progression of BCa [2] with increased EMT transcription factors (EMT-TFs) including Snail, Zeb-1, Twist and Slug, and altered expression of factors involved in cell–cell interaction such as E-cadherin, N-cadherin, and vimentin. Multiple lines of evidence indicate that epigenetic regulation play an important role in BCa cell EMT [3]. By demethylating histone 3 lysine 4 (H3K4), LSD1 represses gene expression transcriptionally [4, 5]. LSD1 can simultaneously up- and down-regulate the expression of a wide spectrum of genes involved in a variety of biologic processes such as proliferation, stem cell pluripotency, embryonic development, and EMT [7,8,9,10,11]. In the cancers of the prostate [12], lung [13], ovarian [14], and colon [15], LSD1
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