VSTM2A suppresses colorectal cancer and antagonizes wnt signaling receptor LRP6

Yujuan Dong, Yanquan Zhang, Wei Kang, Guoping Wang, Huarong Chen, Akira Higashimori, Geicho Nakatsu, Minnie Go, Joanna H.M. Tong, Shu Zheng, Ka Fai To, Joseph J.Y. Sung, Xiaoyong Yang, Jun Yu, Simon S.M. Ng

Research output: Contribution to journalArticlepeer-review

24 Scopus citations


Hyperactivation of Wnt/β-catenin signaling pathway is a critical step in colorectal tumorigenesis. In this study, we identified that V-set and transmembrane domain containing 2A (VSTM2A) was a top-downregulated secreted protein that negatively regulated Wnt singling pathways in colorectal cancer (CRC). We investigated the functional mechanisms and clinical implication of VSTM2A in CRC. Methods: Function of VSTM2A was investigated in vitro and in vivo. VSTM2A binding partner was identified by mass spectrometry, immunoprecipitation and Western blot. The clinical impact of VSTM2A was assessed in 355 CRC patients and TCGA cohort. Results: VSTM2A protein was prominently silenced in CRC tumor tissues and cell lines mediated by its promoter hypermethylation. VSTM2A DNA promoter hypermethylation and VSTM2A protein downregulation was associated with poor survival of CRC patients. Ectopic expression of VSTM2A inhibited colon cancer cell lines and organoid growth, induced CRC cells apoptosis, inhibited cell migration and invasion, and suppressed growth of xenograft tumors in nude mice. VSTM2A was released from CRC cells through a canonical secretion pathway. Secreted VSTM2A significantly suppressed Wnt signaling pathway in colon cancer cells. Wnt signaling co-receptor LDL receptor related protein 6 (LRP6) was identified as a cell membrane binding partner of VSTM2A. Using deletion/mutation and immunoprecipitation, we demonstrated that VSTM2A bound to LRP6 E1-4 domain with its IgV domain. VSTM2A suppressed LRP6 phosphorylation in a time and dose dependent manner, and induced LRP6 endocytosis and lysosome-mediated degradation, which collectively contributing to the inactivation of Wnt signaling. Conclusions: VSTM2A is a novel antagonist of canonical Wnt signaling by directly binding to LRP6 and induces LRP6 endocytosis and degradation. VSTM2A is a potential prognostic biomarker for the outcome of CRC patients.

Original languageEnglish
Pages (from-to)6517-6531
Number of pages15
Issue number22
StatePublished - 2019

Bibliographical note

Funding Information:
This project was supported by research funds from National Key R&D Program of China (No. 2018YFC1312100/2018YFC1312102); National Key R&D Program of China (2017YFE0190700); RGC GRF Hong Kong (14111216, 14163817), Science and Technology Program Grant, Shenzhen (JCYJ20170413161534162), Shenzhen Virtual University Park Support Scheme to CUHK Shenzhen Research Institute, and National Natural Science Foundation of China (81871900, 81502436).

Publisher Copyright:
© The author(s).


  • Colorectal cancer prognosis
  • LRP6
  • VSTM2A
  • Wnt signaling

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Pharmacology, Toxicology and Pharmaceutics (miscellaneous)


Dive into the research topics of 'VSTM2A suppresses colorectal cancer and antagonizes wnt signaling receptor LRP6'. Together they form a unique fingerprint.

Cite this