<i>FAS</i> and <i>FASLG</i> Genetic Variants and Risk for Second Primary Malignancy in Patients with Squamous Cell Carcinoma of the Head and Neck

Sun

et al. 2015

Intl Journal of Cancer

Self Cite

Single nucleotide polymorphisms (SNPs) in the promoter region of FAS and FASLG may alter their transcriptional activity. Thus, we determined the associations between four FAS and FASLG promoter variants (FAS1377G>A, rs2234767; 670A>G, rs1800682; FASLG844T>C, rs763110; and 124A>G, rs5030772) and the risk of recurrence of squamous cell carcinoma of the oropharynx (SCCOP). We evaluated the associations between FAS and FASLG genetic variants and the risk of recurrence in a cohort of 1008 patients. The log-rank test and multivariate Cox models were used to evaluate the associations. Compared with patients with common homozygous genotypes of FAS670 and FASLG844 polymorphisms, patients with variant genotypes had lower disease-free survival rates (log-rank P < 0.0001 and P < 0.0001, respectively) and an approximately 3-fold higher risk of SCCOP recurrence (HR, 3.2;95% CI, 2.2–4.6; and HR, 3.1; 95% CI, 2.2–4.4, respectively) after multivariate adjustment. Furthermore, among patients with HPV16-positive tumors, those with variant genotypes of these two polymorphisms had lower disease-free survival rates (log-rank, P < 0.0001 and P < 0.0001, respectively) and a higher recurrence risk than did patients with common homozygous genotypes (HR, 12.9; 95% CI, 3.8–43.6; and HR, 8.1; 95% CI, 3.6–18.6, respectively), whereas no significant associations were found for FAS1377 and FASLG124 polymorphisms. Our findings suggest that FAS670 and FASLG844 polymorphisms modulate the risk of recurrence of SCCOP, particularly in patients with HPV16-positive tumors. Larger studies are needed to validate these results.

Section: Discussioncontrasting

confidence: 91%

Apoptotic variants as predictors of risk of oropharyngeal cancer recurrence after definitive radiotherapy

Sun

et al. 2015

Intl Journal of Cancer

Self Cite

The Journal of Immunology

“…ALPS patients also exhibited increased risk of both hematopoietic and non-hematopoietic cancers (9, 11). Furthermore, FAS and FASL gene promoter polymorphisms are associated with decreased Fas expression level and increased risk of both hematopoietic malignancies and non-hematopoietic carcinoma development in humans (12-14). The Fas protein level is high in normal human colon tissues.…”

Section: Introductionmentioning

confidence: 99%

H3K9 Trimethylation Silences Fas Expression To Confer Colon Carcinoma Immune Escape and 5-Fluorouracil Chemoresistance

Paschall

Yang

et al. 2015

119

The Fas-FasL effector mechanism plays a key role in cancer immune surveillance by host T cells, but metastatic human colon carcinoma often uses silencing Fas expression as a mechanism of immune evasion. The molecular mechanism under FAS transcriptional silencing in human colon carcinoma is unknown. We performed genome-wide ChIP-Sequencing analysis and identified that the FAS promoter is enriched with H3K9me3 in metastatic human colon carcinoma cells. H3K9me3 level in the FAS promoter region is significantly higher in metastatic than in primary cancer cells, and is inversely correlated with Fas expression level. We discovered that verticillin A is a selective inhibitor of histone methyltransferases SUV39H1, SUV39H2 and G9a/GLP that exhibit redundant functions in H3K9 trimethylation and FAS transcriptional silencing. Genome-wide gene expression analysis identified FAS as one of the verticillin A target genes. Verticillin A treatment decreased H3K9me3 level in the FAS promoter and restored Fas expression. Furthermore, verticillin A exhibited greater efficacy than Decitabine and Vorinostat in overcoming colon carcinoma resistance to FasL-induced apoptosis. Verticillin A also increased DR5 expression and overcame colon carcinoma resistance to DR5 agonist drozitumab-induced apoptosis. Interestingly, verticillin A overcame metastatic colon carcinoma resistance to 5-Fluouracil in vitro and in vivo. Using an orthotopic colon cancer mouse model, we demonstrated that tumor-infiltrating cytotoxic T lymphocytes are FasL+ and FasL-mediated cancer immune surveillance is essential for colon carcinoma growth control in vivo. Our findings determine that H3K9me3 of the FAS promoter is a dominant mechanism underlying FAS silencing and resultant colon carcinoma immune evasion and progression.

The Journal of Immunology

“…Furthermore, both the Fas and FasL gene promoters are polymorphic, including a G to A substitution at −1377 bp, and A to G substitution at −670 bp at the Fas gene promoter; and C to T substitution at −844 and −124 A to G substitution at the FasL gene promoter. These polymorphisms diminish transcription factor binding to the Fas and FasL promoter to decrease Fas and FasL expression level, resulting in increased risk of cancer development in humans (14–19). Moreover, a study with a large cohort of human colorectal cancer patient specimens showed that Fas-mediated apoptosis is an important contributor of tumor regression (11).…”

Section: Introductionmentioning

confidence: 99%

Decitabine and Vorinostat Cooperate To Sensitize Colon Carcinoma Cells to Fas Ligand-Induced Apoptosis In Vitro and Tumor Suppression In Vivo

Yang

Torres‐Rouff

Bardhan

et al. 2012

The death receptor Fas and its physiological legend, FasL, regulate apoptosis of cancerous cells, thereby functioning as a critical component of the host cancer immunosurveillance system. To evade Fas-mediated apoptosis, cancer cells often down-regulate Fas to acquire an apoptosis-resistant phenotype, which is a hallmark of metastatic human colorectal cancer. Therefore, targeting Fas resistance is of critical importance in Fas-based cancer therapy and immunotherapy. Here we demonstrated that epigenetic inhibitors, Decitabine and Vorinostat, cooperate to up-regulate Fas expression in the metastatic human colon carcinoma cells. Decitabine also up-regulates BNIP3 and Bik expression, whereas Vorinostat decreased Bcl-xL expression. Altered expression of Fas, BNIP3, Bik and Bcl-xL resulted in effective sensitization of the metastatic human colon carcinoma cells to FasL-induced apoptosis. Using an experimental metastasis mouse model, we further demonstrated that Decitabine and Vorinostat cooperate to suppress colon carcinoma metastasis. Analysis of tumor-bearing lung tissues revealed that a large portion of tumor-infiltrating CD8+ T cells are FasL+, and Decitabine and Vorinostat-mediated tumor suppression efficacy was significantly decreased in Fasgld mice as compared to wt mice, suggesting a critical role of FasL in Decitabine and Vorinostat-mediated tumor suppression in vivo. Consistent with their function in apoptosis sensitization, Decitabine and Vorinostat significantly increased the efficacy of CTL adoptive transfer immunotherapy in an experimental metastasis mouse model. Our data thus suggest that combined modalities of chemotherapy to sensitize the tumor cell to Fas-mediated apoptosis and CTL immunotherapy is an effective approach for the suppression of colon cancer metastasis.