LSD1 Promotes Bladder Cancer Progression by Upregulating LEF1 and Enhancing EMT
LSD1 Promotes Bladder Cancer Progression by Upregulating LEF1 and Enhancing EMT
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LSD1 通过上调 LEF1 和增强 EMT 促进膀胱癌进展
DOI：
10.3389/fonc.2020.01234
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发表时间：
2020-07-28
影响因子：
4.7
通讯作者：
Jiang, Jun
中科院分区：
文献类型：
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作者：
Xie, Qiubo;Tang, Tang;Jiang, Jun
上皮向间充质转化(EMT)是包括膀胱癌在内的大多数肿瘤发生的重要分子机制之一。EMT介导的膀胱癌进展的确切分子机制还远未完成。LSD1是一种组蛋白赖氨酸特异性去甲基酶，已知可促进癌细胞的增殖、转移和化疗耐药。我们在本研究中发现，LSD1在膀胱癌标本中高度上调，特别是在接受化疗的膀胱癌标本中，并且LSD1水平的升高与膀胱癌的分级、转移状况和预后密切相关。抑制或敲除LSD1不仅抑制了EMT过程，也抑制了癌症的进展。从机制上讲，LSD1与β-连环蛋白形成复合体，在转录水平上上调LEF1，从而促进EMT介导的癌症进展。更重要的是，LSD1特异性抑制剂GSK2879552能够在患者来源的肿瘤异种移植中抑制肿瘤进展。这些发现表明，LSD1不仅可以作为预后的生物标志物，而且在膀胱癌的治疗中也是一个有前途的治疗靶点。
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.