SMYD3, short for SET and MYN-domain containing 3, is a member of the SMYD lysine methylase family. It plays a crucial role in the methylation of various histone (such as H3K4, H4K5, H4K20) and non-histone (e.g., VEGFR, HER2, MAP3K2, ER) targets. By modifying these substrates, SMYD3 is involved in regulating epigenetic processes and signaling pathways, which are essential for normal cell function and are also implicated in the development and progression of various diseases, especially cancer [1,2].

In cancer, SMYD3 has been extensively studied. In liver and colon tumors, nuclear-localized SMYD3 acts as a selective transcriptional amplifier of oncogenes and genes related to cell proliferation and metastatic spread [3]. In lung and pancreatic cancer, cytoplasmic SMYD3 potentiates oncogenic Ras/ERK signaling via MAP3K2 methylation [3]. In small cell lung cancer, SMYD3 impedes sensitivity to alkylation damage through RNF113A methylation-phosphorylation cross-talk, and its inhibition can restore sensitivity to alkylating chemotherapy [4]. In HPV-negative head and neck squamous cell carcinoma, SMYD3 represses the tumor-intrinsic interferon response, and its depletion can enhance the influx of CD8+ T cells and sensitivity to anti-programmed death 1 therapy [5]. In prostate cancer, the SMYD3-MAP3K2 signaling axis promotes tumor aggressiveness and metastasis [6]. A meta-analysis also shows that SMYD3 overexpression is significantly associated with poor overall survival, lymph node metastasis, larger tumor size, and advanced TNM stage in various cancers [7].

In conclusion, SMYD3 is a key regulator in multiple biological processes, especially in cancer development and progression. Studies using in vivo models, though not specifically detailed as KO/CKO mouse models in the provided abstracts, have clearly demonstrated its oncogenic role in various cancer types. Understanding SMYD3's functions may provide potential therapeutic targets for cancer treatment.

References:

1. Bottino, Cinzia, Peserico, Alessia, Simone, Cristiano, Caretti, Giuseppina. 2020. SMYD3: An Oncogenic Driver Targeting Epigenetic Regulation and Signaling Pathways. In Cancers, 12, . doi:10.3390/cancers12010142. https://pubmed.ncbi.nlm.nih.gov/31935919/

2. Bernard, Benjamin J, Nigam, Nupur, Burkitt, Kyunghee, Saloura, Vassiliki. 2021. SMYD3: a regulator of epigenetic and signaling pathways in cancer. In Clinical epigenetics, 13, 45. doi:10.1186/s13148-021-01021-9. https://pubmed.ncbi.nlm.nih.gov/33637115/

3. Giakountis, Antonis, Moulos, Panagiotis, Sarris, Michalis E, Hatzis, Pantelis, Talianidis, Iannis. 2016. Smyd3-associated regulatory pathways in cancer. In Seminars in cancer biology, 42, 70-80. doi:10.1016/j.semcancer.2016.08.008. https://pubmed.ncbi.nlm.nih.gov/27554136/

4. Lukinović, Valentina, Hausmann, Simone, Roth, Gael S, Mosammaparast, Nima, Reynoird, Nicolas. . SMYD3 Impedes Small Cell Lung Cancer Sensitivity to Alkylation Damage through RNF113A Methylation-Phosphorylation Cross-talk. In Cancer discovery, 12, 2158-2179. doi:10.1158/2159-8290.CD-21-0205. https://pubmed.ncbi.nlm.nih.gov/35819319/

5. Nigam, Nupur, Bernard, Benjamin, Sevilla, Samantha, Hager, Gordon L, Saloura, Vassiliki. 2023. SMYD3 represses tumor-intrinsic interferon response in HPV-negative squamous cell carcinoma of the head and neck. In Cell reports, 42, 112823. doi:10.1016/j.celrep.2023.112823. https://pubmed.ncbi.nlm.nih.gov/37463106/

6. Ikram, Sabeen, Rege, Apurv, Negesse, Maraki Y, Reynoird, Nicolas, Green, Erin M. 2023. The SMYD3-MAP3K2 signaling axis promotes tumor aggressiveness and metastasis in prostate cancer. In Science advances, 9, eadi5921. doi:10.1126/sciadv.adi5921. https://pubmed.ncbi.nlm.nih.gov/37976356/

7. Wang, Xuan, Liu, Debao, Yang, Jing. . Clinicopathological and Prognostic Significance of SMYD3 in Human Cancers: A Systematic Review and Meta-analysis. In Genetic testing and molecular biomarkers, 26, 331-339. doi:10.1089/gtmb.2021.0199. https://pubmed.ncbi.nlm.nih.gov/35763383/