SETD6, a protein lysine methyltransferase, is involved in multiple biological processes. It plays a role in regulating intracellular signaling pathways, with its methylation activity contributing to normal cellular functions. It is associated with pathways such as NF-κB, Wnt, and Nrf2, and is important for processes like transcription, memory formation, and cell cycle regulation [1,2,5,6,7]. Genetic models, like gene knockout models, can be valuable for studying SETD6's functions.

In HPV-episomal cells, SETD6 methylates Brd4 at lysine 99, which is crucial for E2-Brd4 association and HPV transcriptional activation [1]. In rat dorsal hippocampus, knockdown of Setd6 during memory consolidation interferes with memory-related nuclear factor-κB RELA methylation, H3K9me2 changes, gene expression, and spine morphology, suggesting SETD6 is essential for hippocampus-dependent memory formation [2]. In glioma, SETD6 methylates TWIST1 at chromatin, promoting EMT by attenuating LINC-PINT expression [3]. In lung adenocarcinoma, SETD6 is overexpressed in tumor tissues, promoting malignant behaviors likely through NF-κB and Nrf2 signaling pathways [4]. SETD6-deficient cells progress faster through mitosis due to increased kinase activity of PLK1, revealing its role in regulating mitotic progression [5]. In a FCCTX family, a truncating mutation in SETD6 may contribute to cancer inheritance as the mutant allele acts in a dominant-negative manner [6]. Depletion of SETD6 leads to elevated Nrf2 levels and increased expression of Nrf2 antioxidant target genes, indicating SETD6 is a negative regulator of the oxidative stress response [7]. In breast carcinoma cells, silencing of SETD6 induces cellular proliferation defects and apoptosis, suggesting SETD6 is essential for nuclear receptor signaling and cellular proliferation [8].

In summary, SETD6 is a key regulator in various biological processes, including transcription, memory formation, cell cycle, and stress response. Its dysregulation is associated with diseases such as viral-related cancers, glioma, lung adenocarcinoma, and familial colorectal cancer. Studies using knockout or knockdown models have been crucial in revealing these functions and disease associations, providing insights into potential therapeutic targets.

References:

1. Jose, Leny, Androphy, Elliot J, DeSmet, Marsha. 2022. SETD6 Regulates E2-Dependent Human Papillomavirus Transcription. In Journal of virology, 96, e0129522. doi:10.1128/jvi.01295-22. https://pubmed.ncbi.nlm.nih.gov/36300937/

2. Webb, William M, Irwin, Ashleigh B, Pepin, Mark E, Cash, Andrew E, Lubin, Farah D. 2019. The SETD6 Methyltransferase Plays an Essential Role in Hippocampus-Dependent Memory Formation. In Biological psychiatry, 87, 577-587. doi:10.1016/j.biopsych.2019.05.022. https://pubmed.ncbi.nlm.nih.gov/31378303/

3. Admoni-Elisha, Lee, Elbaz, Tzofit, Chopra, Anand, Feldman, Michal, Levy, Dan. . TWIST1 methylation by SETD6 selectively antagonizes LINC-PINT expression in glioma. In Nucleic acids research, 50, 6903-6918. doi:10.1093/nar/gkac485. https://pubmed.ncbi.nlm.nih.gov/35694846/

4. Xu, Jing, Zhou, Hui, Luo, Ziling, Chen, Jie, Liu, Man. 2023. Investigating the functional role of SETD6 in lung adenocarcinoma. In BMC cancer, 23, 18. doi:10.1186/s12885-022-10476-9. https://pubmed.ncbi.nlm.nih.gov/36604642/

5. Feldman, Michal, Vershinin, Zlata, Goliand, Inna, Elia, Natalie, Levy, Dan. 2019. The methyltransferase SETD6 regulates Mitotic progression through PLK1 methylation. In Proceedings of the National Academy of Sciences of the United States of America, 116, 1235-1240. doi:10.1073/pnas.1804407116. https://pubmed.ncbi.nlm.nih.gov/30622182/

6. Martín-Morales, Lorena, Feldman, Michal, Vershinin, Zlata, Caldés, Trinidad, Levy, Dan. . SETD6 dominant negative mutation in familial colorectal cancer type X. In Human molecular genetics, 26, 4481-4493. doi:10.1093/hmg/ddx336. https://pubmed.ncbi.nlm.nih.gov/28973356/

7. Chen, Ayelet, Feldman, Michal, Vershinin, Zlata, Levy, Dan. 2016. SETD6 is a negative regulator of oxidative stress response. In Biochimica et biophysica acta, 1859, 420-7. doi:10.1016/j.bbagrm.2016.01.003. https://pubmed.ncbi.nlm.nih.gov/26780326/

8. O'Neill, Daniel J, Williamson, Stuart Charles, Alkharaif, Dhuha, Gingras, Anne-Claude, Binda, Olivier. 2014. SETD6 controls the expression of estrogen-responsive genes and proliferation of breast carcinoma cells. In Epigenetics, 9, 942-50. doi:10.4161/epi.28864. https://pubmed.ncbi.nlm.nih.gov/24751716/