Background
Oral cancer is one of the most common solid malignancy worldwide, accounting for approximately 3% of all malignancies in both sexes. Several etiologic risks including human papillomavirus infection, smoking, and heavy alcohol consumption have been increasingly recognized for oral carcinogenesis [
1,
2]. The overweighing majority of oral cancer is classified as squamous cell carcinoma (SCC) and mostly arises from tongue followed by mouth floor, buccal as well as gingiva [
1,
2]. Thus, tongue SCC (TSCC) is a representative cancer subtype of OSCC and accounts for a large fraction of OSCC cases. The past decades have witnessed tremendous progress in multi-modal therapy against TSCC. However, the long-term survival for patients with TSCC is not markedly improved, especially for those with advanced diseases [
3]. These facts underscore the highly aggressive nature of TSCC and the unresolved challenge for diagnostic and therapeutic management of this malignancy in the clinic. Until now, few biomarkers have been equivocally established for diagnostic and prognostic management of tongue cancer. Therefore, the identification of the new biomarkers and therapeutic targets for TSCC is paramount and urgent for clinicians to improve the patients’ prognosis.
Epigenetic abnormality is a hallmark of human cancer and greatly contributes to cancer initiation and progression [
4]. Mounting evidence has established that several epigenetic modulators have been identified as key mediators driving tumorigenesis by serving as pro-oncogenes or tumor suppressor genes. Moreover, these epigenetic modulators hold great promise as putative therapeutic targets against cancer largely owing to their pervasive roles in gene regulation as well as the inherent reversible nature of epigenetic alternations [
5]. Among these epigenetic modulators underlying tumorigenesis, several members of polycomb group (PcG) proteins have stood out as essential participators of malignant transformation as well as promising targets for cancer therapeutic intervention. Previous studies have revealed that the PcG components usually assemble in stable multi-protein complexes together with additional factors to maintain their target genes in a transcriptionally repressive state [
6]. In brief, two polycomb repressive complexes (PRC1 and PRC2) harbor multiple core members to execute their functions by histone modifications and in turn induce gene silencing [
7]. Our previous studies and others have offered strong evidence that multiple members of PcG such as Bmi1 and EZH2 are bona fide oncogenes contributing to tumorigenesis in diverse sites throughout the whole body including tongue and their overexpression associates with cancer aggressiveness and poor prognosis in a broad spectrum of human cancer including tongue cancer [
8‐
10]. Notably, suppressor of zest 12 (SUZ12) is one of the core component of PRC2, which is essential for PRC2-mediated gene silencing by generating trimethylation on lysine 27 residue of histone H3 (H3K27me3) [
11]. However, the biological roles and associated molecular mechanisms of SUZ12 underlying tumor development are just beginning to be elucidated. For example, SUZ12 has been found to be frequently overexpressed in several solid cancers including colorectal, ovarian and non-small lung cancer, etc. [
12‐
14]. Furthermore, its aberrant overexpression commonly associated with tumor aggressive behaviors, advanced clinicopathological features and decreased survival, thus suggesting potential roles of SUZ12 as a novel cancer biomarker and a putative oncogene [
12‐
14]. However, to the best of our knowledge, the expression of SUZ12 and its clinicopathological significance in TSCC have not been established yet.
Herein, we sought to investigate the expression of SUZ12 protein in primary human TSCC specimens and identify potential relationship between its abundance and clinicopathological features as well as patients’ survival.
Discussion
The epigenetic modifiers, PRC1 and 2, regulate gene expression by modifying chromatin structure and are intricately implicated in various biological and pathological processes including stem cell plasticity, cell differentiation and proliferation as well as tumorigenesis [
6,
17,
18]. Previous studies have suggested that the SUZ12, one of the core components of PRC2, might be an oncogene driving tumorigenesis and serve as a novel diagnostic biomarker and therapeutic target for cancer treatment [
13,
18,
19]. Herein we investigated the expression pattern of SUZ12 in primary TSCC and determined its clinicopathological relevance and prognostic significance for patients with TSCC. Our findings reveal that SUZ12 is aberrantly overexpressed in a significant fraction of TSCC and its overexpression associates with aggressive clinicopathological features and unfavorable prognosis.
Tongue tumorigenesis in human is characterized by multiple and consecutive histopathological stages from normal epithelial to invasive SCC which is driven by oncogenes activation and tumor suppressor inactivation [
2]. In particular, epigenetic inactivation of tumor suppressor genes contributes to initiation and progression of tongue cancer [
20]. Among them, these chromatin modifiers like the polycomb members have been increasingly recognized as key players during tumorigenesis. They usually facilitate cancer initiation, overgrowth and metastasis, and also have been identified as therapeutic targets with remarkable translational potential [
21]. We and others have provided evidence that several members of PcG such as EZH2 and Bmi1 are aberrantly upregulated in tongue cancer and associated with aggressiveness and poor prognosis [
8,
10]. Notably, highly elevated SUZ12 has been found in bladder, gastric, non-small cell lung and colorectal cancer, etc. [
12,
13,
19]. In line with these previous finding, our data reveal that SUZ12 is significantly elevated in a large subset of human TSCC, thus supporting the notion that SUZ12 might be an bona fide oncogene fostering tumorigenesis in diverse sites throughout the body including tongue. To the best of our knowledge, this might be the first study to uncover the abnormal expression pattern of SUZ12 in TSCC. However, due to the limited number of patients enrolled here, more number of patients from multiple institutions is needed to definitively establish the overexpression pattern of SUZ12 as well as its diagnostic utility in tongue cancer.
Accumulating evidence has demonstrated that SUZ12 overexpression significantly associated with aggressiveness in multiple human cancers [
13]. For example, elevated SUZ12 is significantly associated with tumor size, lymph node metastasis and clinical stages in non-small cell lung cancer and colorectal cancer [
13,
14]. Similarly, our findings reveal that SUZ12 overexpression significantly associates with cervical lymph nodes metastasis in TSCC, while the associations between other clinicopathological parameters and SUZ12 don’t reach statistical significance. Noticeably, Our findings and others point to an interesting link and positive association between SUZ12 expression and cancer metastasis irrespective of cancer origin and primary site [
13,
22,
23]. Complementary to this notion, previous studies have demonstrated that the metastasis-regulator Snail recruits SUZ12 to the CDH1 promoter and represses E-cadherin expression, thus in turn triggers EMT and cancer metastasis [
24,
25]. Moreover, targeting SUZ12 by gene knockdown suppresses the migratory and invasive properties of cancer cells and inhibits tumor metastasis in animal models [
13,
25]. Taken together, we propose that SUZ12 is a novel cancer biomarker of TSCC which significantly associates with cervical node metastasis. It remains an interesting question to determine the expression level of SUZ12 in the metastatic lesions and its clinical significance, and further unravel its associated mechanistic underpins during cancer metastatic spread.
The past decades have witnessed tremendous progress in diagnosis and treatment for TSCC. However, the 5-year survival rate remains disappointing, suggesting that accurate prognostic prediction is a great challenge but highly beneficial in the clinic [
3]. Previous studies have revealed that SUZ12 expression associates with patients’ prognosis and is identified as a key independent prognostic predictor for patients with epithelial ovarian cancer, non-small cell lung cancer and gastric cancer [
12,
13]. For example, Li et al. [
12] have reported that expression of SUZ12 positively correlates with Ki67 and predicts shorter overall survival in patients with ovarian cancer. Consistent with these findings, our results indicate that patients with high SUZ12 have significantly shorter survival as compared to those with low SUZ12. Furthermore, SUZ12 expression is identified as an independent prognostic factor affecting survival of patients with TSCC. Thus, the expression status of SUZ12 might offer valuable information about patients’ prognosis and indication for effective follow-up management.
A line of evidence has uncovered that SUZ12 is critically involved in tumorigenesis by promoting cell proliferation, migration and metastasis while suppressing apoptosis [
12,
13,
25]. Moreover, SUZ12 together with miR-200b is important for cancer stem cell growth and invasive ability in breast cancer cells [
26]. In particular, pharmacologic or genetic disruption of SUZ12 inhibited cell proliferation and invasion, and disrupted the maintenance of cancer stem cell both in vitro and in vivo [
12,
13,
26,
27]. These abovementioned findings strongly suggest that SUZ12 serves as not only a novel cancer biomarker with diagnostic and prognostic values, but also a viable therapeutic target. Therefore, it remains an open and interesting question to unravel the roles of SUZ12 and its regulatory network during tongue tumorigenesis and to develop efficient approaches to therapeutically targeting SUZ12 in cancer.
Authors’ contributions
HH and YW performed the experimental study, data collection and analysis and manuscript writing. ZL, YZ and WZ analyzed the IHC data. DW, TL, JY and YW performed surgery and collected the data of patients. JC conceived and supervised the whole project. All authors read and approved the final manuscript