The Role of DAXX in Cancer Development and Progression (G1616)

Target Name: DAXX

NCBI ID: G1616

DAXX

The Role of DAXX in Cancer Development and Progression

Cancer remains one of the leading causes of mortality worldwide, with new cases continuing to rise. The development of innovative therapies, specifically targeted towards the unique molecular characteristics of cancer cells, has revolutionized cancer treatment. One such drug target that has gained significant attention is DAXX.

Understanding DAXX

DAXX, short for Death Domain-Associated Protein, is a multifunctional protein that plays a critical role in various cellular processes. Initially identified as a protein involved in apoptosis, recent studies have shed light on its broader roles, specifically in cancer.

Regulation of Cell Death

One of the fundamental functions of DAXX is its involvement in cell death regulation. It acts as an adaptor protein, bridging the interaction between apoptosis regulatory proteins such as Fas-associated protein with death domain (FADD) and apoptotic signaling pathways. DAXX is believed to regulate apoptotic processes by modulating the activity of pro-apoptotic and anti-apoptotic factors.

The dysregulation of apoptosis is a hallmark of cancer, enabling cancer cells to evade programmed cell death and promote tumor survival. As a result, targeting DAXX has emerged as a promising therapeutic strategy for inducing cell death specifically in cancer cells.

Tumor Suppression Mechanisms

In addition to its role in apoptosis, DAXX also functions as a tumor suppressor. It is involved in regulating the activity of tumor suppressor proteins, such as p53 and BRCA1. DAXX acts as a co-repressor for p53, a well-known tumor suppressor that induces cell cycle arrest and apoptosis in response to DNA damage. By interacting with p53, DAXX enhances its transcriptional activity, leading to the inhibition of cancer cell proliferation.

Furthermore, DAXX interacts with BRCA1, a critical protein involved in DNA repair. This interaction promotes the efficient repair of DNA damage, thereby preventing the accumulation of genetic aberrations that can drive cancer development.

Alterations in DAXX Expression in Cancer

Numerous studies have highlighted the dysregulation of DAXX expression in various types of cancer. The downregulation of DAXX has been observed in several solid tumors, including glioblastoma, melanoma, and lung cancer. This decrease in DAXX expression often correlates with poor clinical outcomes, increased tumor aggressiveness, and drug resistance.

On the other hand, DAXX upregulation has also been reported in certain cancers, such as pancreatic neuroendocrine tumors. In these cases, elevated DAXX expression contributes to enhanced tumor growth and drug resistance through mechanisms that are yet to be fully understood.

Exploiting DAXX as a Biomarker and Therapeutic Target

Given the significant roles played by DAXX in cancer development and progression, it has emerged as a promising biomarker and therapeutic target.

Biomarker Potential

The dysregulation of DAXX expression in multiple cancer types suggests its potential as a prognostic and predictive biomarker. Various research studies have shown that DAXX expression levels correlate with overall survival rates, disease recurrence, and response to therapy. Therefore, measuring DAXX expression levels in tumor tissues or biological fluids can provide valuable information for personalized treatment decisions and monitoring of treatment response.

Therapeutic Target

Exploiting DAXX as a therapeutic target has garnered attention from researchers and pharmaceutical companies. Small molecules and peptides that can modulate DAXX activity are being developed as potential anticancer agents. These compounds aim to restore normal apoptotic processes, rescue tumor suppressor functions, or interfere with DAXX-mediated signaling pathways that promote cancer cell survival and proliferation.

Moreover, recent advancements in gene-editing technologies, such as CRISPR-Cas9, offer new possibilities for targeted manipulation of DAXX expression. By precisely modifying DAXX levels in cancer cells, it may be possible to restore normal cellular processes and enhance the effectiveness of existing therapies.

Conclusion

DAXX, a multifunctional protein involved in cell death regulation and tumor suppression, has emerged as an exciting drug target and biomarker in cancer research. The dysregulation of DAXX expression in cancer makes it a promising marker for prognosis and response to therapy, while the development of DAXX-targeted therapies holds great potential for future cancer treatments. Continued research and clinical trials are needed to fully exploit the therapeutic potential of targeting DAXX in cancer therapy.

Protein Name: Death Domain Associated Protein

Functions: Transcription corepressor known to repress transcriptional potential of several sumoylated transcription factors. Down-regulates basal and activated transcription. Its transcription repressor activity is modulated by recruiting it to subnuclear compartments like the nucleolus or PML/POD/ND10 nuclear bodies through interactions with MCSR1 and PML, respectively. Seems to regulate transcription in PML/POD/ND10 nuclear bodies together with PML and may influence TNFRSF6-dependent apoptosis thereby. Inhibits transcriptional activation of PAX3 and ETS1 through direct protein-protein interactions. Modulates PAX5 activity; the function seems to involve CREBBP. Acts as an adapter protein in a MDM2-DAXX-USP7 complex by regulating the RING-finger E3 ligase MDM2 ubiquitination activity. Under non-stress condition, in association with the deubiquitinating USP7, prevents MDM2 self-ubiquitination and enhances the intrinsic E3 ligase activity of MDM2 towards TP53, thereby promoting TP53 ubiquitination and subsequent proteasomal degradation. Upon DNA damage, its association with MDM2 and USP7 is disrupted, resulting in increased MDM2 autoubiquitination and consequently, MDM2 degradation, which leads to TP53 stabilization. Acts as histone chaperone that facilitates deposition of histone H3.3. Acts as targeting component of the chromatin remodeling complex ATRX:DAXX which has ATP-dependent DNA translocase activity and catalyzes the replication-independent deposition of histone H3.3 in pericentric DNA repeats outside S-phase and telomeres, and the in vitro remodeling of H3.3-containing nucleosomes. Does not affect the ATPase activity of ATRX but alleviates its transcription repression activity. Upon neuronal activation associates with regulatory elements of selected immediate early genes where it promotes deposition of histone H3.3 which may be linked to transcriptional induction of these genes. Required for the recruitment of histone H3.3:H4 dimers to PML-nuclear bodies (PML-NBs); the process is independent of ATRX and facilitated by ASF1A; PML-NBs are suggested to function as regulatory sites for the incorporation of newly synthesized histone H3.3 into chromatin. In case of overexpression of centromeric histone variant CENPA (as found in various tumors) is involved in its mislocalization to chromosomes; the ectopic localization involves a heterotypic tetramer containing CENPA, and histones H3.3 and H4 and decreases binding of CTCF to chromatin. Proposed to mediate activation of the JNK pathway and apoptosis via MAP3K5 in response to signaling from TNFRSF6 and TGFBR2. Interaction with HSPB1/HSP27 may prevent interaction with TNFRSF6 and MAP3K5 and block DAXX-mediated apoptosis. In contrast, in lymphoid cells JNC activation and TNFRSF6-mediated apoptosis may not involve DAXX. Shows restriction activity towards human cytomegalovirus (HCMV). Plays a role as a positive regulator of the heat shock transcription factor HSF1 activity during the stress protein response (PubMed:15016915)

The "DAXX Target / Biomarker Review Report" is a customizable review of hundreds up to thousends of related scientific research literature by AI technology, covering specific information about DAXX comprehensively, including but not limited to:
•   general information;
•   protein structure and compound binding;
•   protein biological mechanisms;
•   its importance;
•   the target screening and validation;
•   expression level;
•   disease relevance;
•   drug resistance;
•   related combination drugs;
•   pharmacochemistry experiments;
•   related patent analysis;
•   advantages and risks of development, etc.
The report is helpful for project application, drug molecule design, research progress updates, publication of research papers, patent applications, etc. If you are interested to get a full version of this report, please feel free to contact us at BD@silexon.ai

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