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


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.

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Data availability

The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.



Chicken embryo chorioallantoic membrane


Patient-derived xenograft


Colorectal cancer


RNA-binding protein


Endothelial cell


Tumor-conditioned medium


Microvessel density


Transcription factor


Notch1 intracellular domain


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This research was supported in part by the National Natural Science Foundation of China (82073133, and 82072729), the Scientific research project of Jiangsu Health Committee (ZDA2020005), the Natural Science Foundation of Jiangsu Province (BK20211606 and BK20191154), and the Xuzhou Medical Leading Talents Training Project (XWRCHT20210034).

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Authors and Affiliations



JS and YZ: conceived the study and participated in the study design. YZ, LZ, and HS: performed cell culture, tubule formation, HUVEC migration, qPCR, Western blot, IP, RIP, luciferase assay, and ChIP assay. YZ and HS: performed bioinformatics analysis, IHC staining, and pathological diagnosis. LZ, YXX: carried out CAM experiments. LZ, YXX, and JYZ: constructed animal models. CL, JQW, and XXS: contributed to clinical sample collection, follow-up clinical data analysis. Primer design and plasmid construction were carried out by YZ, TJ, and HS. YZ, LZ, and HS analyzed the data, sorted the charts, and wrote the manuscript. The final draft was read and approved by all authors.

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Correspondence to Hu Song or Jun Song.

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Zhang, Y., Zhou, L., Xu, Y. et al. Targeting SMYD2 inhibits angiogenesis and increases the efficiency of apatinib by suppressing EGFL7 in colorectal cancer. Angiogenesis (2022).

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  • Colorectal cancer
  • Angiogenesis
  • SMYD2
  • Methylation
  • Apatinib