Targeting the TREX Complex: A Novel Approach to Trigger Immunogenic Cell Death (ICD) in Cancer

A recent study by researchers from Uppsala University, Sweden, has identified zinc finger CCCH containing 11A (ZC3H11A), a component of the TREX (TRanscription and EXport) complex, as a potential target for cancer therapies aimed at inducing immunogenic cell death (ICD) and enhancing anti-tumor immune responses.

The TREX Complex is a Key Regulator of mRNA Export and Cancer Progression

The TREX (TRanscription and EXport) complex plays a critical role in cancer development and progression by influencing mRNA export, cell survival, proliferation, and genomic stability. TREX components exhibit variable expression patterns across different cancer types, with THOC1 reduced in skin and testicular cancers but elevated in lung, ovarian, colon, and breast cancers, where higher levels correlate with increased tumor size and metastasis. TREX is essential for mRNA export, and its dysregulation in cancer cells can affect the export of specific mRNAs, potentially influencing the expression of oncogenes or tumor suppressors. Reducing TREX component levels can inhibit mRNA export of pro-survival and proliferative factors, thereby reducing oncogenic phenotypes. Certain TREX components are associated with specific cancers, such as ALY in oral squamous cell carcinoma and GANP in lymphoma. TREX’s involvement in these processes makes it a potential therapeutic target, and ongoing research aims to understand how targeting TREX components could affect tumor growth and progression. Additionally, TREX plays a role in maintaining genomic stability by preventing DNA damage and regulating the cell cycle, and its dysregulation in cancer cells may contribute to genomic instability, a hallmark of cancer.

ZC3H11A in mRNA Export, Immune Modulation, and Viral Pathogenesis

ZC3H11A is a conserved RNA-binding protein with three CCCH zinc finger domains, found in all vertebrates. It plays key roles in mRNA metabolism, stress response, viral replication, and immune signaling. As part of the TREX complex, it facilitates mRNA export from the nucleus, especially during stress. ZC3H11A is upregulated in stress conditions and is exploited by viruses like HIV-1 and influenza for replication. It regulates the NF-κB pathway, influencing immune responses. The protein interacts with mRNA processing components and binds to purine-rich sequences in cellular and viral transcripts. ZC3H11A is crucial for cellular homeostasis under stress and represents a potential target for antiviral therapies.

The Role of ZC3H11A in Cancer Progression

ZC3H11A plays a significant role in cancer progression and development, with its expression levels being elevated in various cancer types. While its expression patterns can vary depending on the cancer, ZC3H11A is primarily localized in the nucleus of tumor cells and linked to poor prognosis in most cancers, although this can differ by cancer type. The protein is involved in critical processes such as mRNA processing and export, which are often dysregulated in cancer, and may help cancer cells adapt to stress within the tumor microenvironment. Additionally, certain cancer-associated viruses, like human cytomegalovirus (HCMV), can influence ZC3H11A expression, suggesting a potential connection between virus-induced cancers and ZC3H11A function. Given its involvement in these cancer-related processes, ZC3H11A is being investigated as a potential therapeutic target. Ongoing research is exploring its regulatory mechanisms in virus-infected tumors, its interaction with the immune system, and its effects on tumor growth, particularly in animal models. Although ZC3H11A’s exact functions in different cancer types are still being studied, its role in mRNA processing, stress response, and cancer progression makes it a promising target for cancer therapy.

ZC3H11A Knockdown Induced Immunogenic Apoptosis

ZC3H11A knockdown in B16 melanoma cells enhanced antigen presentation and type-I interferon production. RNA profiling revealed upregulation of antigen presentation and interferon response pathways, with reduced cell cycle activity. MHC-I expression and IFN-β secretion increased, while cell viability decreased. Similar effects were observed in HCmel12 and CT26 cells, suggesting that ZC3H11A knockdown promotes cell death and enhances immune response pathways.

Knockdown of ZC3H11A induces immunogenic apoptosis, characterized by increased CRT (calreticulin) exposure and ATP release, which are key markers of immunogenic cell death. This form of apoptosis significantly enhanced the phagocytic activity, activation, and maturation of immature dendritic cells (imDCs). Similar effects were observed in other cancer cell lines, such as HCmel12 and CT26. These findings suggest that ZC3H11A knockdown triggers immunogenic apoptosis across multiple cell lines, potentially modulating immune responses and enhancing anti-tumor immunity.

In Vivo Targeting of ZC3H11A Reduces Tumor Growth and Improves Survival in Animal Models

Targeting ZC3H11A in murine melanoma models significantly reduced tumor growth and improved survival in mice. Mice treated with intratumoral administrations of ASO showed decreased tumor volume and enhanced survival rates. RNA profiling of treated tumors revealed upregulation of pathways related to apoptosis, cytotoxicity, antigen presentation, IFN signaling, and immune cell migration, with a concurrent downregulation of cell proliferation pathways.

To evaluate the potential of this therapeutic strategy against human cancers, human HeLa cells with a ZC3H11A knockout (HeLa-KO-ZC3) were engineered and injected into athymic nude mice. Mice with ZC3H11A knockout tumors exhibited slower tumor growth and improved survival compared to those injected with control HeLa cells (HeLa-CT, Cas9 nonsense gRNA). These findings strongly support ZC3H11A as a valid target for cancer therapy, although effective targeting of ZC3H11A remains a significant challenge.

Conclusions

Targeting ZC3H11A in cancer therapy shows promise in inhibiting tumor growth by enhancing anti-tumor immunity. This approach strengthens antigen presentation through MHC-I, stimulates the interferon response, and induces immunogenic apoptosis.

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For Further Reading

1. Targeting ZC3H11A elicits immunogenic cancer cell death through augmentation of antigen presentation and interferon response. Molecular Therapy-Nucleic Acids; 2024; Published online.
2. The role of TREX in gene expression and disease. Biochem. J., 2016; 473:2911–2935. 
3. The Nuclear Pore Complex and mRNA Export in Cancer. Cancers (Basel); 2020; 13:42. 
4. Multiple nuclear-replicating viruses require the stress-induced protein ZC3H11A for efficient growth. Proc. Natl. Acad. Sci. USA., 2018; 115–E3816.
5. CHTOP in Chemoresistant Epithelial Ovarian Cancer: A Novel and Potential Therapeutic Target. Front. Oncol., 2019; 9:557. 
6. Analysis of the mRNA export protein ZC3H11A in HCMV infection and pan-cancer. Front. Microbiol. Sec. Virology; 2023; 14 – 2023. 

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