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Characterization of the transcriptional repressor SAMD1 in hepatocellular carcinoma and pancreatic ductal adenocarcinoma
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...
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| Format: | Doctoral Thesis |
| Language: | English |
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Philipps-Universität Marburg
2023
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| Online Access: | PDF Full Text |
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| Summary: | 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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| DOI: | 10.17192/z2023.0600 |