Abstract
Lysine-specific demethylase 1 (LSD1), which specifically demethylates histone H3 lysine 4 (H3K4) and lysine 9 (H3K9), is dysregulated in several cancers. We found that ectopic expression of LSD1 in cervical cancer cells promoted invasion and metastasis in vitro and in vivo, reduced the expression of the epithelial marker E-cadherin, and induced the expression of the mesenchymal marker, Vimentin. By contrast, LSD1 knockdown had the opposite effect and attenuated the HPV16 E7-induced epithelial-mesenchymal transition (EMT). We proposed a novel mechanism, whereby LSD1 is recruited to the Vimentin promoter and demethylates H3K4me1 and H3K4me2. Notably, HPV16 E7 enhanced the expression of LSD1, formed a complex with LSD1, and suppressed LSD1 demethylase activity by hindering the recruitment of LSD1 to the Vimentin promoter. Thus, LSD1 is a primary and positive regulator of the HPV16 E7-induced EMT and an attractive therapeutic target for alleviating HPV16 E7-induced EMT and tumor metastasis.
Highlights
According to the World Health Organization, cervical cancer is one of the most common cancers in women worldwide [1], especially in China and developing countries
High levels of Lysine-specific demethylase 1 (LSD1) protein have been found in several types of solid tumors and have been associated with poor prognosis; for instance, LSD1 expression gradually increases during tumor progression from pre-invasive ductal carcinoma in situ to invasive ductal breast carcinoma [16]
Overexpression of LSD1 protein correlates with disease progression and poor prognosis in hepatocellular carcinoma patients [29], and promotes recurrence and elevated VEGF-A expression in prostate cancer patients [30]
Summary
According to the World Health Organization, cervical cancer is one of the most common cancers in women worldwide [1], especially in China and developing countries. There were more than 98,900 new cases of cervical cancer and 30,500 deaths reported in China in 2015[2]. Human papilloma virus (HPV), a small, circular, double-stranded DNA virus infecting epithelial cells, has been reported to be necessary but not sufficient to induce tumorigenesis in host squamous epithelial cells [3, 4]. Persistent high-risk HPV infection of the cervix is the defining feature of cervical cancer [5]. The major oncogenes, E6 and E7, cooperate to control the cell cycle and promote cell growth by inhibiting the activity of important tumor suppresser proteins, including p53, retinoblastoma (Rb) family members, PDZ domaincontaining proteins, etc [6]. E7 overcomes proliferation www.impactjournals.com/oncotarget arrest by sequestering Rb from E2F complexes, disrupting a series of signaling pathways and facilitating tumor growth, invasion or metastasis [7, 8]. Despite the clear and complete understanding of these mechanisms, the success of HPV-targeted treatments has not improved
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