Nuclear factor one transcription factors as epigenetic regulators in cancer

Abstract

Tumour heterogeneity poses a distinct obstacle to therapeutic intervention. While the initiation of tumours across various physiological systems is frequently associated with signature mutations in genes that drive proliferation and bypass senescence, increasing evidence suggests that tumour progression and clonal diversity is driven at an epigenetic level. The tumour microenvironment plays a key role in driving diversity as cells adapt to demands imposed during tumour growth, and is thought to drive certain subpopulations back to a stem cell-like state. This stem cell-like phenotype primes tumour cells to react to external cues via the use of developmental pathways that facilitate changes in proliferation, migration and invasion. Because the dynamism of this stem cell-like state requires constant chromatin remodelling and rapid alterations at regulatory elements, it is of great therapeutic interest to identify the cell-intrinsic factors that confer these epigenetic changes that drive tumour progression. The nuclear factor one (NFI) family are transcription factors that play an important role in the development of many mammalian organ systems. While all four family members have been shown to act as either oncogenes or tumour suppressors across various cancer models, evidence has emerged implicating them as key epigenetic regulators during development and within tumours. Notably, NFIs have also been shown to regulate chromatin accessibility at distal regulatory elements that drive tumour cell dissemination and metastasis. Here we summarize the role of the NFIs in cancer, focusing largely on the potential mechanisms associated with chromatin remodelling and epigenetic modulation of gene expression.

Stilbenoid‐Mediated Epigenetic Activation of Semaphorin 3A in Breast Cancer Cells Involves Changes in Dynamic Interactions of DNA with DNMT3A and NF1C Transcription Factor

“…A response element for NF1C was further found in 80% of hypomethylated loci within “hypomethylated RSV targets,” a group of genes hypomethylated in both MCF10CA1h and MCF10CA1a cells (Table S3, Supporting Information). Additionally, transcription factors from NF1 family have been implicated as key epigenetic regulators in cancer possibly through regulating chromatin accessibility . NF1C was specifically reported to have a tumor suppressor role in breast cancer .…”

“…Additionally, transcription factors from NF1 family have been implicated as key epige-netic regulators in cancer possibly through regulating chromatin accessibility. [49] NF1C was specifically reported to have a tumor suppressor role in breast cancer. [50] For these reasons, we proceeded with experimentally testing whether stilbenoid-mediated changes in DNA methylation near predicted NF1C binding site within the SEMA3A promoter affected binding of this potentially important transcription factor.…”

Nuclear factor I X is a recurrent target for HPV16 insertions in anal carcinomas

“…The NFI gene family has therefore dual functionality in acting not only as classical transcription factors, but also as epigenetic modifiers. Regarding their role in oncogenesis, NFI s have been found to act as oncogenes and tumor suppressors across a wide range of cancer types . In addition to abnormal morphogenesis related to germinal mutations, NFIX has been more specifically implicated in the development of breast carcinoma, through the formation of a fusion protein with Mast kinase, and in esophageal carcinoma through tumor suppression properties .…”

Prognostic significance of NFIA and NFIB in esophageal squamous carcinoma and esophagogastric junction adenocarcinoma

“…The nuclear factor I (NFI) family, initially found to function in adenoviral DNA replication, consists of four genes ( NFIA , NFIB , NFIC , and NFIX ). These genes encode nuclear factors that bind to TTGGC(N5)GCCAA sequence as homo‐ or heterodimers to activate or suppress gene transcription depending on the cellular context and regulatory region . The NFIs were then demonstrated to play crucial roles in the development of many organ systems such as the central nervous system and lung .…”