Promoter Hypermethylation Promotes the Binding of Transcription Factor NFATc1, Triggering Oncogenic Gene Activation in Pancreatic Cancer

Abstract

Studies have indicated that some genes involved in carcinogenesis are highly methylated in their promoter regions but nevertheless strongly transcribed. It has been proposed that transcription factors could bind specifically to methylated promoters and trigger transcription. We looked at this rather comprehensively for pancreatic ductal adenocarcinoma (PDAC) and studied some cases in more detail. Some 2% of regulated genes in PDAC exhibited higher transcription coupled to promoter hypermethylation in comparison to healthy tissue. Screening 661 transcription factors, several were found to bind specifically to methylated promoters, in particular molecules of the NFAT family. One of them—NFATc1—was substantially more strongly expressed in PDAC than control tissue and exhibited a strong oncogenic role. Functional studies combined with computational analyses allowed determining affected genes. A prominent one was gene ALDH1A3, which accelerates PDAC metastasis and correlates with a bad prognosis. Further studies confirmed the direct up-regulation of ALDH1A3 transcription by NFATc1 promoter binding in a methylation-dependent process, providing insights into the oncogenic role of transcription activation in PDAC that is promoted by DNA methylation.

Transient receptor potential vanilloid type 4 (TRPV4) promotes tumorigenesis via NFAT4 activation in nasopharyngeal carcinoma

“…Furthermore, NFAT4 knockdown, and treatment with CsA and FK506 impaired the growth of NPC cells. Other studies have also supported the critical role of the NFAT pathway in cancer progression ( Mancini and Toker 2009 ; Kim et al, 2019 ; Wu et al, 2021 ). Consistent with this, NFAT4 expression was higher in NPC tissues, and correlated positively with that of TRPV4.…”

Epigenetic Effects of Resveratrol on Oncogenic Signaling in Breast Cancer

“…Hence, the main focus in epigenetic pharmacology was on developing strategies that will inhibit DNA methylation and remove aberrant methylation marks from tumor suppressor genes to produce anti-cancer effects. However, technological advances allowed for genome-wide studies of DNA methylation patterns in cancer, which showed that some hypermethylated promoters are actually associated with active transcription rather than silencing [ 7 ]. In pancreatic cancer, this phenomenon was mechanistically explained by the preferential binding of the NFATc1 transcription factor to hypermethylated DNA, followed by the activation of the transcriptional machinery [ 7 ].…”

“…However, technological advances allowed for genome-wide studies of DNA methylation patterns in cancer, which showed that some hypermethylated promoters are actually associated with active transcription rather than silencing [ 7 ]. In pancreatic cancer, this phenomenon was mechanistically explained by the preferential binding of the NFATc1 transcription factor to hypermethylated DNA, followed by the activation of the transcriptional machinery [ 7 ]. Recent decades of genome-wide studies of the DNA methylation landscape in cancer also show that DNA hypomethylation of promoters and other gene regulatory regions, like enhancers, is as prevalent in cancer as hypermethylation [ 8 , 9 , 10 ].…”