FAS rs2234767 and rs1800682 polymorphisms jointly contributed to risk of colorectal cancer by affecting SP1/STAT1 complex recruitment to chromatin

Abstract

FAS rs2234767 (−1377 G>A), rs1800682 (−670 A>G) and FASLG rs763110 (−844 C>T) promoter polymorphisms can influence transcriptional activities of the genes and thus multiple tumors susceptibility. To investigate their association with risk of colorectal cancer (CRC), the three SNPs were genotyped in 878 cases and 884 controls and the results showed that the FAS rs2234767 and rs1800682 were in a high linkage disequilibrium (LD) with each other (D’ = 0.994) and jointly contributed to an increased risk of CRC (without vs. with rs2234767 GG/rs1800682 AA genotypes, adjusted OR = 1.30, 95% CI = 1.05 − 1.61). In vivo ChIP assays evaluated the effect of rs2234767 and rs1800682 on recruitment of SP1 and STAT1, respectively, to chromatin. The results showed SP1 interacting specifically with STAT1 recruited to their respective motifs for transcriptional activation. The mutant alleles rs2234767 A and rs1800682 G jointly affected coupled SP1 and STAT1 recruitment to chromatin. The interplay between SP1 and STAT1 was critical for the functional outcome of rs2234767 and rs1800682 in view of their high LD. In conclusion, the FAS rs2234767 and rs1800682 polymorphisms were in high LD with each other, and they jointly contributed to an increased risk of CRC by altering recruitment of SP1/STAT1 complex to the FAS promoter for transcriptional activation.

A novel mechanism of rs763110 polymorphism contributing to cervical cancer risk by affecting the binding affinity of C/EBPβ and OCT1 complex to chromatin

“…Additionally, siRNA knockdown experiments showed that C/EBPβ played a more important role than the function of OCT1. Similarly, we demonstrated that the rs2234767 and rs1800682 polymorphisms might contribute to the risk of colorectal cancer by regulating the SP‐1/STAT1 complex to the FAS gene promoter region . Therefore, we speculate that the interactions among the different transcription factors may play a significant role in the regulation of gene expression.…”

Sp1‐mediated epigenetic dysregulation dictates HDAC inhibitor susceptibility of HER2‐overexpressing breast cancer

“…e ). Sp1, a reported FAS regulator, as well as HDAC1 and p300, were detected on FAS promoter (Fig. f ).…”

Distinct role of the <em>Fas </em>rs1800682 and <em>FasL </em>rs763110 polymorphisms in determining the risk of breast cancer among Han Chinese women

“…The Fas rs1800682 polymorphism is located in a STAT1 binding element on the Fas promoter, which has been linked to the downregulation of Fas expression. 22 The FasL gene rs763110 polymorphism lies within a putative binding motif for the CAAT/enhancer-binding protein β-transcription factor. 41 Our results suggest that the Fas rs1800682 SNP may be associated with an increased risk of breast cancer, while the FasL rs763110 polymorphism may decrease breast cancer risk.…”

“…A large number of studies revealed that Fas/FasL gene polymorphisms are associated with susceptibility to various types of cancer, including cervical, 11 – 14 pharyngeal, 15 – 17 digestive, 18 – 22 and breast cancer. 23 – 28 Further studies demonstrated that circulating, soluble Fas (s Fas ) can inhibit Fas -mediated apoptosis by neutralizing the FasL or the anti- Fas antibodies, 29 while increased levels of s Fas have been observed in serum from patients with breast cancer.…”