SMYD3, a member of the SMYD lysine methylase family, is a chromatin modifier. It methylates various histone (such as H3K4, H4K5, H4K20) and non-histone (like VEGFR, HER2, MAP3K2, ER) targets. It is involved in epigenetic regulation and signaling pathways, playing a significant role in carcinogenesis. Its upregulation has been proposed as a prognostic marker in various solid cancers [1,2].

SMYD3-associated regulatory pathways have been studied in different cancers. In liver and colon tumors, nuclear-localized SMYD3 acts as a transcriptional amplifier of oncogenes and genes related to cell proliferation and metastasis [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 restores vulnerability to chemotherapy [4]. In HPV-negative head and neck squamous cell carcinoma, SMYD3 represses the tumor-intrinsic interferon response, and its depletion increases sensitivity to anti-PD-1 therapy [5]. In prostate cancer, the SMYD3-MAP3K2 signaling axis promotes tumor aggressiveness and metastasis [6]. A meta-analysis showed 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 cancer. Its functions in promoting tumorigenesis, metastasis, and chemoresistance across different cancer types are well-demonstrated through in vivo and clinical studies. Understanding the role of SMYD3 in these disease conditions, as revealed by functional studies including gene knockout-related models, may provide new therapeutic strategies 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/