Signal Integrator Function of CXXC5 in Cancer

Immunology Genetics Life Sciences Cell Biology Oncology Medicine
CXXC5 cell signaling cancer targeting therapy epigenetic regulation Wnt/β-catenin pathway TGF-β/BMP pathway

Signal Integrator Function of CXXC5 in Cancer

Academic Background

CXXC5 (CXXC-type zinc finger protein 5) is a member of the ZF-CXXC protein family and plays a pivotal role in signal integration and information transfer within the cellular signaling network. By regulating multiple signaling pathways (such as Wnt/β-catenin, TGF-β/BMP, ATM/p53, etc.) and gene expression, CXXC5 is involved in processes such as cell proliferation, differentiation, apoptosis, and metabolism. Its abnormal expression or dysfunction is associated with various pathological processes, particularly the development and progression of cancer. However, the specific mechanisms of CXXC5 in cancer and its potential therapeutic value have not yet been fully elucidated. Therefore, this article aims to comprehensively review the functions of CXXC5 in cellular signaling networks, especially its role in cancer, and explore its potential as a therapeutic target.

Source of the Paper

This article was co-authored by Zihao An, Jiepu Wang, Chengzuo Li, and Chao Tang from the National Clinical Research Center for Child Health at the Children’s Hospital of Zhejiang University School of Medicine. The paper was published in 2025 in the journal Cell Communication and Signaling under the title “Signal Integrator Function of CXXC5 in Cancer.” It is a review article that systematically summarizes the functions of CXXC5 in cellular signaling networks and its multifaceted roles in cancer.

Main Content of the Paper

1. Gene and Protein Structure of CXXC5

The CXXC5 gene is located on human chromosome 5q31.2 and consists of 11 exons and 10 introns. Its protein is composed of 322 amino acids with a molecular weight of 32.98 kDa. The core domain of the CXXC5 protein is the ZF-CXXC domain, which can bind to unmethylated CpG islands, thereby exerting epigenetic regulatory functions. Additionally, CXXC5 contains a nuclear localization sequence (NLS) and a “KTXXXI” motif that interacts with the Dvl (Dishevelled) protein. These domains collectively determine the multifunctionality of CXXC5 in cellular signaling networks.

2. Integrative Function of CXXC5 in Signaling Networks

As a signal integrator, CXXC5 regulates multiple signaling pathways (such as Wnt/β-catenin, TGF-β/BMP, ATM/p53, etc.) and gene expression, participating in processes such as cell proliferation, differentiation, apoptosis, and metabolism. For example, CXXC5 forms a negative feedback loop by inhibiting the Wnt/β-catenin signaling pathway, thereby regulating cell proliferation and tissue homeostasis. Simultaneously, CXXC5 influences cell differentiation and tissue development by modulating the TGF-β/BMP signaling pathway.

2.1 Wnt/β-Catenin Signaling Pathway

CXXC5 is a crucial negative feedback regulator of the Wnt/β-catenin signaling pathway. In human colon cancer cells and neural stem cells, activation of the Wnt signaling pathway upregulates CXXC5 expression. CXXC5, in turn, interacts with the Dvl protein to inhibit the nuclear translocation of β-catenin and the transcription of downstream target genes, forming a negative feedback loop. This mechanism plays a significant role in processes such as skin repair, hair regeneration, and angiogenesis.

2.2 TGF-β/BMP Signaling Pathway

CXXC5 acts as a positive feedback regulator in the TGF-β/BMP signaling pathway. In human umbilical vein endothelial cells (HUVECs) and neural stem cells, activation of the BMP4 signaling pathway upregulates CXXC5 expression. CXXC5 then promotes the phosphorylation and nuclear translocation of Smad proteins, facilitating the transmission of the TGF-β/BMP signaling pathway. This mechanism is crucial in processes such as angiogenesis and bone development.

3. Dual Role of CXXC5 in Cancer

CXXC5 exhibits a dual role in cancer, acting either as a tumor suppressor or a tumor promoter, depending on the cancer type and cellular context.

3.1 Tumor Suppressor Function

In acute myeloid leukemia (AML) and gastric cancer (GC), downregulation of CXXC5 expression is closely associated with tumorigenesis and progression. For example, in AML, CXXC5 inhibits leukemia cell proliferation by suppressing the Wnt signaling pathway and regulating p53-dependent DNA damage responses. Additionally, in hepatocellular carcinoma (HCC), CXXC5 promotes cell cycle arrest and apoptosis by enhancing the TGF-β signaling pathway, exerting a tumor-suppressive effect.

3.2 Tumor Promoter Function

In breast cancer (BC), prostate cancer (PCA), and ovarian cancer (OC), high expression of CXXC5 is associated with tumor progression and poor prognosis. For instance, in BC, CXXC5 promotes tumor cell proliferation and immune escape by inhibiting the TSC1/mTOR signaling pathway. Furthermore, in prostate cancer, CXXC5 recruits TET2 and the androgen receptor (AR) to promote the transcription of non-canonical AR target genes, thereby mediating tumor cell drug resistance.

4. Potential Therapeutic Value of CXXC5

As a signal integrator, CXXC5 holds significant potential value in cancer therapy. Targeting the expression or function of CXXC5 can regulate multiple signaling pathways, thereby inhibiting tumor growth and metastasis. For example, designing small molecule peptides to target the interaction between CXXC5 and Dvl can activate the Wnt/β-catenin signaling pathway, promoting skin repair and hair regeneration. Additionally, the dual role of CXXC5 in cancer suggests that combination therapies may be more effective strategies.

Significance and Value of the Paper

This article systematically reviews the functions of CXXC5 in cellular signaling networks and its multifaceted roles in cancer, providing a comprehensive perspective on understanding the biological functions of CXXC5 and its role in diseases. As a signal integrator, CXXC5 plays a crucial role in cancer, tissue repair, and metabolic regulation, offering significant scientific value and clinical application potential. Future research can further explore the specific mechanisms of CXXC5 in different cellular contexts and develop novel therapeutic strategies targeting CXXC5.

Highlights Summary

  1. Multifunctionality: CXXC5 regulates multiple signaling pathways (such as Wnt/β-catenin, TGF-β/BMP, ATM/p53, etc.), playing a crucial role in cell proliferation, differentiation, apoptosis, and metabolism.
  2. Dual Role: CXXC5 can act as either a tumor suppressor or a tumor promoter in cancer, depending on the cancer type and cellular context.
  3. Therapeutic Potential: As a signal integrator, CXXC5 holds significant potential value in cancer therapy, and targeting its expression or function may lead to novel therapeutic strategies.

This article provides a comprehensive review of CXXC5 research and lays an important foundation for future basic research and clinical applications.