MAP9 loss triggers chromosomal instability, initiates colorectal tumorigenesis, and is associated with poor survival of patients with colorectal cancer

Shiyan Wang, Junzhe Huang, Chuangen Li, Liuyang Zhao, Chi Chun Wong, Jianning Zhai, Yunfei Zhou, Wen Deng, Yong Zeng, Shanshan Gao, Yanquan Zhang, Guoping Wang, Xin Yuan Guan, Hong Wei, Sunny H. Wong, Housheng H. He, Jerry W. Shay, Jun Yu

Research output: Contribution to journalArticlepeer-review

10 Scopus citations


Purpose: Chromosomal instability (CIN) is a common phenomenon in colorectal cancer, but its role and underlying cause remain unknown. We have identified that mitotic regulator microtubule-associated protein 9 (MAP9) is a critical regulator of CIN in colorectal cancer. We thus studied the effect of MAP9 loss on colorectal cancer in Map9-knockout mice and in cell lines. Experimental Design: We generated colon epithelial–specific Map9-knockout mice and evaluated colorectal cancer development. Effect of Map9 knockout on colorectal cancer progression was determined in chemical or ApcMin/þ-induced colorectal cancer. Molecular mechanism of MAP9 was determined using spectral karyotyping, microtubule assays, and whole-genome sequencing (WGS). Clinical significance of MAP9 was examined in 141 patients with CRC. Results: Spontaneous colonic tumors (9.1%) were developed in colon epithelium–specific Map9-knockout mice at 17 months, but none was observed in wild-type littermates. Map9 deletion accelerated colorectal cancer formation both in ApcMin/þ mice and azoxymethane-treated mice, and reduced survival in ApcMin/þ mice. Mechanistically, MAP9 stabilized microtubules and mediated mitotic spindle assembly. MAP9 also maintained the spindle pole integrity and protected K-fiber from depolymerization at spindle poles. MAP9 loss induced severe mitosis failure, chromosome segregation errors, and aneuploidy, leading to transformation of normal colon epithelial cells. WGS confirmed enhanced CIN in intestinal tumors from Map9 knockout ApcMin/þ mice. In patients with colorectal cancer, MAP9 was frequently silenced and its downregulation was associated with poor survival. Conclusions: MAP9 is a microtubule stabilizer that contributes to spindle stability and inhibits colorectal tumorigenesis, supporting the role of MAP9 as a tumor suppressor for preventing CIN in colorectal cancer.

Original languageEnglish
Pages (from-to)746-757
Number of pages12
JournalClinical Cancer Research
Issue number3
StatePublished - Feb 1 2020

Bibliographical note

Publisher Copyright:
© 2019 American Association for Cancer Research.

ASJC Scopus subject areas

  • General Medicine


Dive into the research topics of 'MAP9 loss triggers chromosomal instability, initiates colorectal tumorigenesis, and is associated with poor survival of patients with colorectal cancer'. Together they form a unique fingerprint.

Cite this