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

ABSTRACT: 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.

SUBMITTER: Cao W

PROVIDER: S-EPMC4924734 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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

Cao Wei W Liu Jiannan J Xia Ronghui R Lin Lu L Wang Xu X Xiao Meng M Zhang Chenping C Li Jiang J Ji Tong T Chen Wantao W

Oncotarget 20160301 12

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 met ...[more]

PMID: 26908444

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Project description:Recurrent/metastatic head and neck cancer remains a devastating disease with insufficient treatment options. We investigated the MET receptor tyrosine kinase as a novel target for the treatment of head and neck squamous cell carcinoma (HNSCC). MET/phosphorylated MET and HGF expression was analyzed in 121 tissues (HNSCC/normal) by immunohistochemistry, and in 20 HNSCC cell lines by immunoblotting. The effects of MET inhibition using small interfering RNA/two small-molecule inhibitors (SU11274/PF-2341066) on signaling, migration, viability, and angiogenesis were determined. The complete MET gene was sequenced in 66 head and neck cancer tissue samples and eight cell lines. MET gene copy number was determined in 14 cell lines and 23 tumor tissues. Drug combinations of SU11274 with cisplatin or erlotinib were tested in SCC35/HN5 cell lines. Eighty-four percent of the HNSCC samples showed MET overexpression, whereas 18 of 20 HNSCC cell lines (90%) expressed MET. HGF overexpression was present in 45% of HNSCC. MET inhibition with SU11274/PF-2341066 abrogated MET signaling, cell viability, motility/migration in vitro, and tumor angiogenesis in vivo. Mutational analysis of 66 tumor tissues and 8 cell lines identified novel mutations in the semaphorin (T230M/E168D/N375S), juxtamembrane (T1010I/R988C), and tyrosine kinase (T1275I/V1333I) domains (incidence: 13.5%). Increased MET gene copy number was present with >10 copies in 3 of 23 (13%) tumor tissues. A greater-than-additive inhibition of cell growth was observed when combining a MET inhibitor with cisplatin or erlotinib and synergy may be mediated via erbB3/AKT signaling. MET is functionally important in HNSCC with prominent overexpression, increased gene copy number, and mutations. MET inhibition abrogated MET functions, including proliferation, migration/motility, and angiogenesis. MET is a promising, novel target for HNSCC and combination approaches with cisplatin or EGFR inhibitors should be explored.

Project description:The bromodomain and extraterminal family members are epigenetic readers and transcriptional coactivators which are critically involved in various biological processes including tumorigenesis. BRD4 has been increasingly appreciated as a key oncogene and promising anticancer target. Here, we sought to characterize the expression of BRD4 and its tumorigenic roles as well as therapeutic targeting in HNSCC. Methods: Expression of BRD4 mRNA and protein was determined by bioinformatics interrogation of publically available databases, primary HNSCC samples and 4NQO-induced HNSCC animal model. The tumorigenic roles of BRD4 in HNSCC were evaluated by genetic and pharmacological approach in vitro and in vivo. Therapeutic efficiency of BRD4 targeting by JQ1 was assessed in three preclinical models including xenograft model, 4NQO-induced model and patients-derived xenograft model. Gene candidates responsible for therapeutic effects of JQ1 were identified by transcriptional profiling in HNSCC cells after JQ1 exposure. Results: Significant upregulation of BRD4 was found in primary HNSCC samples and 4NQO-induced HNSCC model. Its overexpression associated with aggressive clinicopathological features and inferior overall and disease-free survival. BRD4 depletion by genetic silencing or pharmacological inhibition impaired cell proliferation, migration and invasion and reduced tumor growth and metastasis in vivo. Transcriptional profiling of HNSCC cells following JQ1 exposure identified hundreds of genes which might mediated its antitumor effects and enriched in cancer-relevant pathways. A novel prognostic risk score derived from JQ1-regulated genes was developed to stratify patients into subgroups with favorable or inferior prognosis. Conclusions: Our findings reveal that BRD4 serves as a novel and critical mediator underlying tumorigenesis and a robust prognostic biomarker in HNSCC. Therapeutic targeting of BRD4 represents a potent and promising strategy against HNSCC.

Dataset Information

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

Publications

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

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