Epigenetics of SFRP1: The Dual Roles in Human Cancers

Abstract

Secreted frizzled-related protein 1 (SFRP1) is a gene that belongs to the secreted glycoprotein SFRP family. SFRP1 has been classified as a tumor suppressor gene due to the loss of expression in various human cancers, which is mainly attributed by epigenetic inactivation via DNA methylation or transcriptional silencing by microRNAs. Epigenetic silencing of SFRP1 may cause dysregulation of cell proliferation, migration, and invasion, which lead to cancer cells formation, disease progression, poor prognosis, and treatment resistance. Hence, restoration of SFRP1 expression via demethylating drugs or over-expression experiments opens the possibility for new cancer therapy approach. While the role of SFRP1 as a tumor suppressor gene is well-established, some studies also reported the possible oncogenic properties of SFRP1 in cancers. In this review, we discussed in great detail the dual roles of SFRP1 in cancers—as tumor suppressor and tumor promoter. The epigenetic regulation of SFRP1 expression will also be underscored with additional emphasis on the potentials of SFRP1 in modulating responses toward chemotherapeutic and epigenetic-modifying drugs, which may encourage the development of novel drugs for cancer treatment. We also present findings from clinical trials and patents involving SFRP1 to illustrate its clinical utility, extensiveness of each research area, and progression toward commercialization. Lastly, this review provides directions for future research to advance SFRP1 as a promising cancer biomarker.

EZH2 regulates sFRP4 expression without affecting the methylation of sFRP4 promoter DNA in colorectal cancer cell lines

“…The expression levels of sFRP4 were downregulated by more than nine-fold in the CRC cell lines compared with the control cell line. (21). The transcriptional expression levels of components of the Wnt signaling pathway were assessed using gene array analysis of whole genome expression in SW1116, SW480, HCT116 and CCC-HIE-2 cells.…”

“…Over the past several decades, advances have been made in the understanding of cancer epigenetics, particularly for aberrant DNA methylation, microRNA and non-coding RNA dysregulation, and alterations in histone modification states (14). sFRPs have been recognized for their potential to sequester Wnt ligands away from their receptor complexes and ultimately antagonize Wnt signaling (4,11,21). Analysis of sFRP hypermethylation may have diagnostic and prognostic value for the detection and management of CRC (24,26).…”

A single cell atlas of the healthy breast tissues reveal clinically relevant clusters of breast epithelial cells

“…Although cluster 0 and 2 appeared as a continuum of cells, significant differences in gene expression are evident (Figure 1D and 2B). For example, while all luminal progenitor cells expressed Secreted Fizzled Related Protein 1 (SFRP1), a modulator of Wnt signaling (Baharudin et al, 2020), genes such as SLP1, ANXA1, RARRES1, KLK5, and KRT15 were enriched in cluster 2. KRT14 and KRT17 expression were enriched in cluster 2 but not in cluster 0.…”

Plasma-Derived Extracellular Vesicles Convey Protein Signatures That Reflect Pathophysiology in Lung and Pancreatic Adenocarcinomas

“…In esophageal, lung, bladder and oral cancers, NID2 methylation and reduced tissue expression are observed [43], suggesting biomarker context of NID2 may diverge in tumor tissue and EV compartments. SFRP1 (Secreted frizzled-related protein 1) is a glycoprotein modulator of Wnt-signaling that has been observed to play both tumor suppressor and oncogenic roles in a number of human cancers and to also be subject to epigenetic regulation via DNA methylation or microRNA transcriptional silencing [44]. A recent study demonstrated functional relevance of exosome-associated SFRP family proteins and that human lung cancer cells take up SFRP-containing exosomes, whereby SFRPs co-localize with β-catenin in both the cytoplasm and nucleus to mediate β-catenin/TCF-mediated transcription of Wnt target genes known to effect cancer stem cell properties [45].…”