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

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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.

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Data availability

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

Abbreviations

CAM:

Chicken embryo chorioallantoic membrane

PDX:

Patient-derived xenograft

CRC:

Colorectal cancer

RBP:

RNA-binding protein

EC:

Endothelial cell

TCM:

Tumor-conditioned medium

MVD:

Microvessel density

TF:

Transcription factor

N1-ICD:

Notch1 intracellular domain

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Acknowledgements

Not applicable.

Funding

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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Author notes

  1. Yi Zhang, Lei Zhou and Yixin Xu have contributed equally to this work.

Authors and Affiliations

  1. Department of General Surgery, The Affiliated Hospital of Xuzhou Medical University, No. 99, Huaihai West Road, Xuzhou, 221002, Jiangsu, China

    Yi Zhang, Yixin Xu, Tao Jiang, Jiaqi Wang, Chao Li, Xiaoxiong Sun, Hu Song & Jun Song

  2. The Graduate School, Xuzhou Medical University, Xuzhou, Jiangsu, China

    Yi Zhang, Lei Zhou, Jingyu Zhou, Chao Li & Xiaoxiong Sun

  3. Institute of Digestive Diseases, Xuzhou Medical University, Xuzhou, Jiangsu, China

    Lei Zhou, Jingyu Zhou & Jun Song

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  1. Yi Zhang
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  3. Yixin Xu
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Contributions

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 26, 1–18 (2023). https://doi.org/10.1007/s10456-022-09839-4

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