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Study reveals role of DCAF1 protein in colon cancer development via EZH2 phosphorylation

Study reveals role of DCAF1 protein in colon cancer development via EZH2 phosphorylation
Study reveals role of DCAF1 protein in colon cancer development via EZH2 phosphorylation

 


DDB1 and CUL4-associated factor 1 (DCAF1) were first identified as proteins that interact with the human immunodeficiency virus 1 (HIV-1) virion-associated protein (Vpr) and regulate cell cycle and cell proliferation. Although most studies involving DCAF1, also known as the HIV-1 Vpr-binding protein (VprBP), report its adapter function in the Cullin 4 A E3 ubiquitin ligase complex, recent studies suggest that DCAF1’s intrinsic Kinase activity has been reported and H2AT120 is the primary phosphorylation target of DCAF1.

study: Phosphorylation and stabilization of EZH2 by DCAF1/VprBP cause aberrant gene silencing in colon cancer. Image Credit: Lukasz Pawl Sczepanski / Shutterstock.com

Background

Gene expression profiling demonstrated a gene-selective corepressor function of DCAF1 associated with targeting and silencing of growth-regulatory genes in cancer cells. Growth regulatory genes are inactivated by DCAF1, which is dependent on H2AT120 phosphorylation (H2AT120p). This inactivation is based on a point mutation at T120 in H2A that renders DCAF1 unable to repress chromatin transcription.

The transrepression potential of DCAF1 in cancer cells can be eliminated by kinase-killing mutations. Thus, H2AT120p-dependent mechanisms are linked to DCAF1 function to maintain an inactive chromatin state and trigger oncogenic transformation.

Higher expression of DCAF1 and elevated H2AT120p levels have been observed in several types of cancer, especially colon cancer. Several studies have demonstrated the importance of DCAF1 kinase activity in tumorigenesis and the importance of DCAF1-mediated H2AT120p in inactivating growth-regulatory genes. A small molecule inhibitor known as B32B3 has been shown to inhibit DCAF1 kinase activity and tumor growth in organoid and xenograft models.

It is essential to understand whether phosphorylation of non-histone proteins is required for oncogenic events promoted by DCAF1. This helps to elucidate the existence of post-translational mechanisms associated with the activation of oncogenic cell signaling.

Enhancer of Zeste Homolog 2 (EZH2) is a highly conserved histone lysine methyltransferase that causes trimethylation of nucleosomal histone H3 at lysine 27 (H3K27me3). EZH2 has been found to be overexpressed or mutated in many types of cancer, appears to be involved in tumor development and progression, and has a poor clinical prognosis. Several studies have reported that the enzymatic activity of EZH2 is regulated by numerous post-translational modifications, including phosphorylation.

In breast cancer, EZH2 enzymatic activity toward H3K27 is attenuated by AMPK-mediated phosphorylation at T311, which subsequently triggers cytoplasmic localization and translocation of EZH2. Furthermore, EZH2 phosphorylation is associated with repression of tumor suppressor genes.

The precise mechanisms involved in regulating EZH2 phosphorylation that affect tumorigenic progression remain unclear.

About research

Recent Nature Communications Studies have revealed that DCAF1 is overexpressed and phosphorylates EZH2 in colon cancer cells.

Mass spectrometry analysis identified T367 of EZH2 as the key phosphorylation site of DCAF1. This finding was further validated using a newly developed EZH2T367 phosphorylation (EZH2T367p)-specific antibody.

In colon cancer, DCAF1 is found to be overexpressed and catalyzes H2AT120p to inactivate genes involved in regulating cell growth and proliferation. In this study, the possibility of additional her-DCAF1 functions through non-histone substrates is investigated.

Identifying associations between DCAF1 and non-histone modifications may provide better insight into oncogenic signaling pathways. This knowledge will enable the development of more effective strategies for treating colon and other types of cancer.

Investigation result

In the current study, researchers elucidated the underlying mechanism by which DCAF1 influences EZH2T367p during colon cancer development, demonstrated in this study.
To this end, DCAF1-mediated EZH2T367p was found to stimulate cancer cell proliferation through accumulation of EZH2 protein and activation of EZH2 enzymatic activity that catalyzes H3K27me3. Subsequent inactivation of growth-regulated genes by H3K27me3 causes uncontrolled cell proliferation and growth.

DCAF1-mediated EZH2T367p modulates the strength and nature of how EZH2 interacts with other components of the Polycomb repressive complex 2 (PRC2) complex. Ultimately, EZH2 enhances her H3K27 stability and histone methyltransferase (HMT) activity. In particular, T367p was found to be a critical factor for EZH2 stability. This allows effective regulation of EZH2 protein levels.

Upregulation of DCAF1 was observed in colon cancer patient samples and correlated with EZH2T367p levels. Furthermore, low-level expression of p38 was distributed throughout the nucleus and cytoplasm of colon cancer cell lines. In the future, biological and functional analyzes of DCAF1 and p38 are needed to better understand the specific roles of DCAF1 and p38 in colon cancer.

The current study not only identified EZH2T367p as a biomarker for predicting colon cancer, but also provided a new approach to treat this disease. For example, targeting DCAF1 kinase activity to EZH2 can effectively prevent colon cancer development.

The DCAF1 inhibitor B32B3 was able to inhibit the uncontrolled cell proliferation associated with colon cancer. moreover, alive, Experiments revealed that the combination of Taz and B32B3 effectively inhibited colon tumorigenesis with minimal side effects on healthy colon cells.

Conclusion

DCAF1-mediated EZH2T367p appears to be oncogenic because inhibition/knockdown of DCAF1 reactivates a large set of tumor suppressor genes that prevent cancer cells from growing. Organoid and xenograft models reveal that effective targeting of DCAF1 and EZH2 via pharmacological agents can cause oncogenic gene silencing and impair the ability to limit colon tumor growth Did.

Journal reference:

  • Ghate, NB, Kim, S., Shin, Y. and others. (2023) EZH2 phosphorylation and stabilization by DCAF1/VprBP cause aberrant gene silencing in colon cancer. Nature Communications 14, 2140. doi:10.1038/s41467-023-37883-1.

Sources

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2/ https://www.news-medical.net/news/20230418/Study-reveals-DCAF1-proteins-role-in-colon-cancer-development-through-EZH2-phosphorylation.aspx

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