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.

有证据表明，CXXC型锌指（ZF-CXXC）蛋白5（CXXC5）是包括雌激素（E2）-雌激素受体α（ERα）在内的各种信号通路的关键调节剂/整合子。由于其ZF-CXXC域，CXXC5被认为是ZF-CXXC家族的成员，该家族与DNA的未甲基化CpG二核苷酸结合，并通过DNA甲基化和/或染色质修饰的酶促活性产生对基因表达至关重要的染色质状态。CXXC5的结构/功能特征仍然未知。建议作为转录和/或表观遗传因子的CXXC5参与细胞增殖，分化和死亡。为了探索CXXC5在E2-ERα介导的细胞事件中的作用，我们通过产生重组蛋白来验证CXXC5确实是未甲基化的CpG结合物。我们发现了CXXC5，尽管缺乏转录激活/抑制功能，但通过调节也受E2调控的独特基因和共同基因的表达来参与E2驱动的细胞增殖。此外，我们发现与ERα的mRNA和蛋白水平相关的CXXC5与ER阳性乳腺癌患者的预后不良有关。因此，作为未甲基化的CpG结合剂的CXXC5有助于E2介导的基因表达，从而导致细胞增殖的调控，并可能促进ER阳性乳腺癌的进展。