FOXC1 Promotes HCC Proliferation and Metastasis by Upregulating DNMT3B to Induce DNA Hypermethylation of CTH Promoter

作者：Zhuoying Lin, Wenjie Huang, Qin He, Dongxiao Li, Zhihui Wang, Yangyang Feng, Danfei Liu, Tongyue Zhang, Yijun Wang, Meng Xie, Xiaoyu Ji, Mengyu Sun, Dean Tian, Limin Xia · 发表于：Research Square · 年份：2020 · DOI：10.21203/rs.3.rs-94035/v1 · 被引用次数：4 · 研究领域：FOXO transcription factor regulation、Epigenetics and DNA Methylation、Cancer-related molecular mechanisms research

Abstract Background: Forkhead box C1 (FOXC1), as a member of the FOX family, is important for promote HCC invasion and metastasis. FOX family protein lays a pivotal role in metabolism. ROS is involved in tumor progression and is associated with the expression of lots of transcription factors. We next explored the mechanism underlying FOXC1 modulating the metabolism and ROS hemostasis in HCC. Methods: We used amino acids arrays to verify which metabolism is involved in FOXC1-induced HCC. The kits were used to detect the ROS levels in HCC cells with over-expression or down-expression of FOXC1. After identified the downstream target genes and candidate pathway which regulated by FOXC1 during HCC progression in vitro and in vivo , we used western blot, immunohistochemistry, bisulfite genomic sequencing, methylation-specific PCR, chromatin immunoprecipitation analysis and luciferase reporter assays to explore the relationship of FOXC1 and downstream genes. Moreover, the correlation between FOXC1 and target genes and the correlation between target genes and the recurrence and overall survival were analyzed in two independent human HCC cohorts. Results: Here, we reported that FOXC1 could inhibit the cysteine metabolism and increase reactive oxygen species (ROS) levels by regulating cysteine metabolism-related genes, cystathionine γ-lyase (CTH). Overexpression of CTH significantly suppressed FOXC1-induced HCC proliferation, invasion and metastasis, while the reduction in cell prolife...