Targeting SMYD2 inhibits angiogenesis and increases the efficiency of apatinib by suppressing EGFL7 in colorectal cancer.

Abstract

Angiogenesis is an essential factor affecting the occurrence and development of solid tumors. SET And MYND Domain Containing 2 (SMYD2) serves as an oncogene in various cancers. However, whether SMYD2 is involved in tumor angiogenesis remains unclear. Here, we report that SMYD2 expression is associated with microvessel density in colorectal cancer (CRC) tissues. SMYD2 promotes CRC angiogenesis in vitro and in vivo. Mechanistically, SMYD2 physically interacts with HNRNPK and mediates lysine monomethylation at K422 of HNRNPK, which substantially increases RNA binding activity. HNRNPK acts by binding and stabilizing EGFL7 mRNA. As an angiogenic stimulant, EGFL7 enhances CRC angiogenesis. H3K4me3 maintained by PHF8 mediates the abnormal overexpression of SMYD2 in CRC. Moreover, targeting SMYD2 blocks CRC angiogenesis in tumor xenografts. Treatment with BAY-598, a functional inhibitor of SMYD2, can also synergize with apatinib in patient-derived xenografts. Overall, our findings reveal a new regulatory axis of CRC angiogenesis and provide a potential strategy for antiangiogenic therapy.

• Authors: Yi Zhang, Lei Zhou, Yixin Xu, Jingyu Zhou, Tao Jiang, Jiaqi Wang, Chao Li, Xiaoxiong Sun, Hu Song, Jun Song
• Journal: Angiogenesis (Angiogenesis) Vol. 26 Issue 1 Pg. 1-18 (02 2023) ISSN: 1573-7209 [Electronic] Germany
• PMID: 35503397 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022. The Author(s), under exclusive licence to Springer Nature B.V.

Chemical References

• apatinib
• Histone-Lysine N-Methyltransferase
• Pyridines
• Transcription Factors
• PHF8 protein, human
• Histone Demethylases
• SMYD2 protein, human
• EGFL7 protein, human
• Calcium-Binding Proteins
• EGF Family of Proteins

Topics

• Humans
• Cell Line, Tumor
• Histone-Lysine N-Methyltransferase (chemistry, genetics, metabolism)
• Pyridines (pharmacology, therapeutic use)
• Transcription Factors (metabolism)
• Colorectal Neoplasms (drug therapy, genetics)
• Histone Demethylases (metabolism)
• Calcium-Binding Proteins
• EGF Family of Proteins (metabolism)