Characterization of the transcriptional repressor SAMD1 in hepatocellular carcinoma and pancreatic ductal adenocarcinoma
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Philipps-Universität Marburg
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Abstract
Until now, the protein SAMD1 had remained largely unexplored. However, recently, we identified SAMD1 as a novel CpG island-binding protein. SAMD1 directly interferes with unmethylated CpG-rich DNA via an atypical winged-helix domain, simultaneously engaging both the major and minor DNA groove. This interaction enables SAMD1 to exert a repressive function on active CpG-islands by recruiting the histone demethylase KDM1A. Moreover, SAMD1 features a SAM domain, facilitating interactions with other SAM domain-containing proteins, and pivotal for homopolymerization. Deletion of SAMD1 in mouse embryonic stem cells leads to augmented H3K4me2 levels and dysregulation of various biological pathways.
SAMD1 exerts a pleiotropic function in cancer, and high SAMD1 expression can correlate with a favorable or unfavorable prognosis. For instance, in hepatocellular carcinoma, the deletion of SAMD1 reduces clonogenicity and promotes a more advantageous transcriptional network. In contrast, in pancreatic ductal adenocarcinoma (PDAC), SAMD1 operates as a repressor of genes related to epithelial-mesenchymal transition. Consequently, in PDAC cells, SAMD1 knockout prompts a shift towards a more mesenchymal phenotype and accelerates migration rates. CDH2, encoding for N-cadherin, is a crucial downstream target of SAMD1 and the main driver of migration after SAMD1 deletion. The DNA binding capability of SAMD1 is modulated by the FBXO11-E3-ubiquitin ligase complex, leading to an overall reduction in SAMD1's chromatin recruitment, specifically in pancreatic ductal adenocarcinoma.
In conclusion, SAMD1's function as a transcriptional repressor is highly context-dependent, as its target genes differ among distinct cell types. Intriguingly, SAMD1 expression often exhibits prognostic significance across various tumor types, positioning it as a promising candidate gene for further exploration in cancer research.
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Created: 2023Issued: 2023-11-27Updated: 2023-11-27
Faculty
Medizin
Publisher
Philipps-Universität Marburg
Language
eng
Data types
DoctoralThesis
Keywords
KDM1APDACHCCSAMD1ChromatinFBXO11cancerKrebs
DDC-Numbers
610
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Simon, Clara (0000-0002-0298-9858): Characterization of the transcriptional repressor SAMD1 in hepatocellular carcinoma and pancreatic ductal adenocarcinoma. : Philipps-Universität Marburg 2023-11-27. DOI: https://doi.org/10.17192/z2023.0600.