CXXC5 as an unmethylated CpG dinucleotide binding protein contributes to estrogen-mediated cellular proliferation

Abstract

Evidence suggests that the CXXC type zinc finger (ZF-CXXC) protein 5 (CXXC5) is a critical regulator/integrator of various signaling pathways that include the estrogen (E2)-estrogen receptor α (ERα). Due to its ZF-CXXC domain, CXXC5 is considered to be a member of the ZF-CXXC family, which binds to unmethylated CpG dinucleotides of DNA and through enzymatic activities for DNA methylation and/or chromatin modifications generates a chromatin state critical for gene expressions. Structural/functional features of CXXC5 remain largely unknown. CXXC5, suggested as transcription and/or epigenetic factor, participates in cellular proliferation, differentiation, and death. To explore the role of CXXC5 in E2-ERα mediated cellular events, we verified by generating a recombinant protein that CXXC5 is indeed an unmethylated CpG binder. We uncovered that CXXC5, although lacks a transcription activation/repression function, participates in E2-driven cellular proliferation by modulating the expression of distinct and mutual genes also regulated by E2. Furthermore, we found that the overexpression of CXXC5, which correlates with mRNA and protein levels of ERα, associates with poor prognosis in ER-positive breast cancer patients. Thus, CXXC5 as an unmethylated CpG binder contributes to E2-mediated gene expressions that result in the regulation of cellular proliferation and may contribute to ER-positive breast cancer progression.

Epigenetic changes with age primes mammary luminal epithelia for cancer initiation

“…We thus propose a mechanism that regulates this binding via the concurrent demethylation of a CpG island in the PPR of CXXC5 and upregulation of ESR1 in luminal-subtype cancers -illustrating a case study of a DNAm priming event present in aged epithelia that creates an opportunity for cancer subtype-specific regulation. Indeed, CXXC5 was shown to participate in E2-driven cellular proliferation through its modulatory effect on the expression of other genes also regulated by E2 [Ayaz et al, 2020]. CXXC5 overexpression, which we establish to be anti-correlated with DNAm at specific CpGs, is associated with poor prognosis of ER+ breast cancers [Ayaz et al, 2020].…”

“…Indeed, CXXC5 was shown to participate in E2-driven cellular proliferation through its modulatory effect on the expression of other genes also regulated by E2 [Ayaz et al, 2020]. CXXC5 overexpression, which we establish to be anti-correlated with DNAm at specific CpGs, is associated with poor prognosis of ER+ breast cancers [Ayaz et al, 2020]. Because CXXC5 binds unmethylated CpG dinucleotides, upregulation of CXXC5 in luminal-subtype cancers could lead to increased positive (self-)regulation by TFs by preventing methylation of CXXC5-occupied promoter regions.…”

Type I Interferon Production of Plasmacytoid Dendritic Cells under Control

“…Another critical regulator of various signaling pathways, the CXXC type zink finger protein 5 (CXXC5) is suggested to act as a transcription factor as well as an epigenetic modifier [54]. It is highly expressed in mouse and human pDCs, where, as an epigenetic regulator it controls DNA methylation and histone modifications [55].…”

A prelude to the proximity interaction mapping of CXXC5

“…CXXC5 is located on chromosome 5q31.2 and encodes a 322 amino-acid protein with a predicted molecular mass of 33 kDa 8 , 10 . Retinoic acid 11 , transforming growth factor-β 12 , bone morphogenetic protein 4 13 , 14 , Wnt3a 15 – 17 , and estrogen 18 – 21 modulate the expression of CXXC5 in experimental systems. The encoded CXXC5 protein alters gene expressions 13 , 17 , 21 – 27 that result in the modulation of diverse cellular events, including signal transduction, DNA damage response, metabolism, proliferation, differentiation, and death 11 – 13 , 15 , 21 , 22 , 24 , 25 , 27 – 30 .…”

“…However, the underlying mechanism by which CXXC5 regulates gene expressions remains unclear. We recently showed that CXXC5 is an unmethylated CpG binder but lacks an intrinsic transcription regulatory function 21 . This raises the possibility that CXXC5 acts as a nucleation factor to establish a transcription state restrictive or permissive for transcription by interacting with transcription factors, transcription co-regulatory proteins, histone, and/or DNA modifiers.…”