Original ArticlesThe histone demethylase LSD1 is a novel oncogene and therapeutic target in oral cancer
Introduction
Oral squamous cell carcinoma (OSCC) is one of the most common cancers worldwide with well-established etiologic factors including smoking abuse and excessive alcohol consumption, human papillomavirus (HPV) infection, and so on [1]. Despite considerable advances in comprehensive and multimodality therapy against this devastating disease over the past decades, however, the long-term survival rate has not been markedly improved, especially in patients with advanced lesions [2]. Locoregional relapse and cervical lymph node metastasis are the most prevalent factors which significantly affect patients' prognosis. Although OSCC initiation and progression are intricately associated with aberrant activation of oncogenes, inactivation of tumor suppressors as well as epigenetic abnormalities, the limited and incomplete information regarding the molecular carcinogenesis of OSCC has hampered the development of biomarkers and therapeutic strategies with high potency and sensitivity [3]. Therefore, further unraveling the molecular mechanisms and identifying novel therapeutic targets are of great importance to improve patient prognosis.
Aberrant epigenetic dysregulation including DNA methylation and histone modification is a hallmark of human cancer [4]. Molecular machinery that governs these epigenetic modifications has become a major focus for targeted therapies for years [5]. Among them, the histone lysine-specific demethylase 1 (LSD1, also known as KDM1A), initially identified in 2004 as the first histone demethylase, has been found to be a bona fide oncogene implicated in a broad spectrum of malignancies [6]. LSD1serves not only as a transcriptional repressor as a core component of CoREST or NuRD co-repressor complexes by mediating the demethylation of H3K4m1/m2, but also as a transcriptional activator via demethylation of H3K9m1/m2 in diverse biological settings [7], [8]. Mounting evidence has well established that LSD1 plays critical roles in diverse fundamental cellular processes including cell proliferation, differentiation, epithelial–mesenchymal transition and stem cell fate determination [9], [10], [11], [12]. Moreover, LSD1 is frequently overexpressed in multiple human cancers including head and neck cancer, and is also associated with aggressive clinicopathological features and adverse patient outcomes [13], [14], [15], [16]. We have reported that LSD1 is aberrantly overexpressed in a majority of tongue squamous cell carcinomas (the most prevalent site for primary OSCC), and significantly associated with aggressive clinicopathological features and unfavorable prognosis [14]. More importantly, pharmacological inhibition or genetic depletion of LSD1 inhibited cancer cell proliferation, differentiation, invasion and migration, and induced tumor recession in animal models, whereas its overexpression contributed to malignant transformation through chromatin modifications in vitro and in vivo [15], [17], [18], [19], [20]. Therefore, these abovementioned findings strongly underscore the importance of LSD1 as an important oncogenic driver and cancer biomarker, and also provide evidence that inhibition of LSD1 may represent an attractive anti-cancer therapeutic approach.
Previous studies have offered intriguing clues that LSD1 functions as an oncogenic driver, novel biomarker as well as a viable therapeutic target in human cancers [16], [18], [21]. However, its expression pattern and detailed biological roles in OSCC remain largely undefined yet. In this study, we sought to assess the LSD1 expression and functions by integrating genetic and pharmacological approaches using OSCC cell lines, animal models and tumor specimens. Our findings here further highlight that LSD1 is critically involved in OSCC tumorigenesis as well as aggressive phenotype, and hold great potential as a novel diagnostic marker and therapeutic target for OSCC.
Section snippets
Materials and methods
Detailed experimental materials, methods and relevant references were described in supplementary experimental procedures. These experiments were performed as described previously with minor modifications [22], [23], [24]. All experimental studies involving humans and animals were approved by the Research Ethic Committee and Animal Research Committee of Nanjing Medical University.
Overexpressed LSD1 in OSCC is associated with aggressive clinicopathological features and patient prognosis
We have provided initial evidence that LSD1 is aberrantly overexpressed in a major fraction of tongue squamous cell carcinoma (the most prevalent site for OSCC), and its overexpression is associated with cancer aggressiveness and unfavorable patient prognosis [14]. To extend these findings, we further evaluated the abundance of LSD1 in OSCC cell lines and tissue samples. The real-time RT-PCR data revealed markedly increased LSD1 transcripts in all OSCC cells relative to the immortalized oral
Discussion
The past decades have highlighted the significance of aberrant epigenetic dysregulation as the key hallmark in human cancer. Such epigenetic alterations are usually reversible and dynamically regulated, thus raising the possibility that they can be therapeutically exploited as novel therapeutic targets against cancer [5]. To date, increasing evidence has linked diverse histone modifications to cancer initiation and progression [31]. Here we provide evidence that the histone demethylase LSD1 is
Conflict of interest
The authors declare that they have no competing interests.
Acknowledgements
This work is financially supported, in whole or in part, by the National Natural Science Foundation of China (81572669), a project funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions (2014-37), Natural Science Foundation of Jiangsu Province (BK20151561), China Postdoctoral Science Foundation (2014M560436), Jiangsu Postdoctoral Science Foundation (1402162C), Jiangsu Creative Training Project for Graduates in Colleges (SJZZ_0119) and Jiangsu Creative
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These authors contributed equally to this work.