Nuclear SMYD3 promotes transcription of cancer-promoting genes including Jak1/2, Myc, and Ctnnb1.
Major finding: Nuclear SMYD3 promotes transcription of cancer-promoting genes including Jak1/2, Myc, and Ctnnb1.
Mechanism: SMYD3 binds to H3K4me3, promoting its recruitment to core promoters of carcinogen-induced genes.
Impact: SMYD3 expression is associated with a poorer outcome in patients with hepatocellular carcinoma.
SET and MYND domain containing 3 (SMYD3) is an oncogenic histone 3 lysine 4 (H3K4) methyltransferase that is overexpressed in multiple tumor types. In RAS-driven lung and pancreas tumors, SMYD3 is exclusively cytoplasmic and promotes KRAS signaling. However, the role of nuclear SMYD3 in other tumor types has not been elucidated. Sarris and colleagues found that, while Smyd3 knockout mice had no abnormalities under normal conditions, they were resistant to the development of chemically induced liver and colon tumors. Smyd3 deletion reduced tumor cell proliferation, and chromatin immunoprecipitation (ChIP) indicated that SMYD3 bound to the promoters of several genes involved in cell-cycle regulation. Additionally, SMYD3 bound to regulatory regions of Myc, Ctnnb1, Jak1, and Jak2 in chemically induced liver tumors, suggesting that SMYD3 induces activation of oncogenic pathways such as JAK–STAT3 signaling. SMYD3 also promoted the epithelial-to-mesenchymal transition and loss of contact inhibition between hepatocytes and intestinal epithelial cells. ChIP sequencing revealed that the majority of SMYD3-occupied sites were also occupied by RNA polymerase II (RNA Pol II), and conversely a high proportion of RNA Pol II sites were also occupied by SMYD3, suggesting that SMYD3 acted as a potentiator of transcription at specific genes upregulated in carcinogenesis. SMYD3 interacted with trimethylated H3K4 (H3K4me3) tails, which was likely responsible, in part, for targeting SMYD3 to transcriptionally active genes. Further, gene expression analysis of patients with hepatocellular carcinoma indicated that elevated SMYD3 expression was associated with a poorer survival. Taken together, these findings indicate that nuclear SMYD3 is required for chemically induced liver and colon tumorigenesis, and suggest that SMYD3 may be a promising therapeutic target in liver and colon tumors.
Sarris ME, Moulos P, Haroniti A, Giakountis A, Talianidis I. Smyd3 is a transcriptional potentiator of multiple cancer-promoting genes and required for liver and colon cancer development. Cancer Cell 2016 Feb 18 [Epub ahead of print].
- ©2016 American Association for Cancer Research.