Estradiol-Estrogen Receptor α Mediates the Expression of the CXXC5 Gene through the Estrogen Response Element-Dependent Signaling Pathway

Abstract

17β-estradiol (E2), the primary circulating estrogen hormone, mediates physiological and pathophysiological functions of breast tissue mainly through estrogen receptor α (ERα). Upon binding to E2, ERα modulates the expression of target genes involved in the regulation of cellular proliferation primarily through interactions with specific DNA sequences, estrogen response elements (EREs). Our previous microarray results suggested that E2-ERα modulates CXXC5 expression. Because of the presence of a zinc-finger CXXC domain (ZF-CXXC), CXXC5 is considered to be a member of the ZF-CXXC family, which binds to non-methylated CpG dinucleotides. Although studies are limited, CXXC5 appears to participate as a transcription factor, co-regulator and/or epigenetic factor in the regulation of cellular events induced by various signaling pathways. However, how signaling pathways mediate the expression of CXXC5 is yet unclear. Due to the importance of E2-ERα signaling in breast tissue, changes in the CXXC5 transcription/synthesis could participate in E2-mediated cellular events as well. To address these issues, we initially examined the mechanism whereby E2-ERα regulates CXXC5 expression. We show here that CXXC5 is an E2-ERα responsive gene regulated by the interaction of E2-ERα with an ERE present at a region upstream of the initial translation codon of the gene.

CXXC5: A novel regulator and coordinator of TGF‐β, BMP and Wnt signaling

“…However, it has also been shown that CXXC5 is overexpressed in ER+ breast cancer and associated with poor prognosis in patients . This is in agreement with the observation that CXXC5 is upregulated by E2‐ERα . Together, these findings suggest that the role of CXXC5 in cancer initiation and progression could rely on cancer types.…”

“…84 This is in agreement with the observation that CXXC5 is upregulated by E2-ERα. 82 Together, these findings suggest that the role of CXXC5 in cancer initiation and progression could rely on cancer types.…”

“…17β‐estradiol (E2)‐ERα signaling plays a critical role in both physiological functions and malignant transformation of breast tissue . E2‐ERα is able to interact with an oestrogen‐responsive element (ERE) (GGTCAnnnTGACC) in the CXXC5 gene promoter, inducing its gene expression in breast cancer cells . Conversely, ThPOK, a zinc‐finger family transcription factor encoded by the Zbtb7b gene, represses CXXC5 gene expression in CD8+ cytotoxic T cells .…”

Estradiol-Induced Epigenetically Mediated Mechanisms and Regulation of Gene Expression

“…CXXC proteins interact with TET2 in the nucleus and demethylate the cytosine residues. Through the activation of both the TET2 enzyme and CXXC4/CXXC5, E2 is a regulator of the hydroxylation of the methylated CpG islands at enhancer regions [63][64][65] (Figure 2a). The second way of E2-induced active demethylation is 5hmC deamination by AID/APOBEC.…”

Overexpression of CXXC5 is a strong poor prognostic factor in ER+ breast cancer

“…We know that 17β-oestradiol (E2) plays an important role in the homeodynamic regulation of breast tissue functions, and the oestrogen receptor (ERα) is the primary transcript expressed in breast tissue. Yasar et al ( 15 ) reported that E2-ERα could regulate the expression of CXXC5. Therefore, we knew that there was a certain relationship between CXXC5 and breast cancer.…”