Research Papers:

X-linked FHL1 as a novel therapeutic target for head and neck squamous cell carcinoma

Wei Cao, Jiannan Liu, Ronghui Xia, Lu Lin, Xu Wang, Meng Xiao, Chenping Zhang, Jiang Li, Tong Ji and Wantao Chen _

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Oncotarget. 2016; 7:14537-14550. https://doi.org/10.18632/oncotarget.7478

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Wei Cao1,2,*, Jiannan Liu1,2,*, Ronghui Xia3, Lu Lin4, Xu Wang1,2, Meng Xiao1,2, Chenping Zhang1,2, Jiang Li3, Tong Ji1,2, Wantao Chen1,2

1Department of Oral Maxillofacial-Head and Neck Oncology, Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China

2Shanghai Research Institute of Stomatology and Shanghai Key Laboratory of Stomatology, Shanghai 200011, China

3Department of Oral Pathology, Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China

4Department of Medical Records, Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China

*These authors contributed to this work equally

Correspondence to:

Wantao Chen, e-mail: [email protected]

Tong Ji, e-mail: [email protected]

Keywords: head and neck squamous cell carcinoma, FHL1, chromosome X, tumor suppressor, prognosis

Received: September 30, 2015     Accepted: January 29, 2016     Published: February 18, 2016


To identify X-linked novel tumor suppressors could provide novel insights to improve prognostic prediction and therapeutic strategy for some cancers. Using bioinformatics and Venn analysis of gene transcriptional profiling, we identified downregulation of X-linked four-and-a-half LIM domains protein 1 (FHL1) gene in head and neck squamous cell carcinoma (HNSCC). FHL1 functions were investigated and confirmed in vitro and in vivo. FHL1 downregulated mechanisms were analyzed in HNSCCs by using methylation specific PCR, bisulfate-based sequencing, 5-Aza-dC treatment and chromatin immunoprecipitation assays. Two independent HNSCC cohorts (the training cohort n = 105 and the validation cohort n = 101) were enrolled to evaluate clinical implications of FHL1 expression by using real-time PCR or immunohistochemistry. FHL1 mRNA and protein expressions were frequently decreased in HNSCCs. FHL1 overexpression or depletion gave rise to suppress or promote cell growth through Cyclin D1, Cyclin E and p27 dysregulations. Abundant occupy of EZH2 or H3K27Me3 was observed in FHL1 promoter except for DNA hypermethylation. Reduced FHL1 mRNA expression was notably associated with poor differentiation (p = 0.020). Multivariate analysis demonstrated FHL1 mRNA expression was identified as independent prognostic predictors of overall survival (OS) (p = 0.036; HR 0.520; Cl, 0.283–0.958) and disease-free survival (DFS) (p = 0.041; HR 0.527; Cl, 0.284–0.975), which was validated by another independent cohort (p = 0.021; HR 0.404; Cl, 0.187–0.871 for OS; p = 0.011; HR 0.407; Cl, 0.203–0.815 for DFS). These results suggest epigenetic silencing of X-linked FHL1 may have an important role in adjuvant therapeutic intervention of HNSCCs and is an independent prognostic factor in patients with HNSCCs.

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