MAP9 Loss Triggers Chromosomal Instability, Initiates Colorectal Tumorigenesis, and Is Associated with Poor Survival of Patients with Colorectal Cancer.

Abstract

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 <i>Map9</i>-knockout mice and in cell lines. We generated colon epithelial-specific <i>Map9</i>-knockout mice and evaluated colorectal cancer development. Effect of <i>Map9</i> knockout on colorectal cancer progression was determined in chemical or <i>Apc^Min ^/+</i> -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. Spontaneous colonic tumors (9.1%) were developed in colon epithelium-specific <i>Map9</i>-knockout mice at 17 months, but none was observed in wild-type littermates. <i>Map9</i> deletion accelerated colorectal cancer formation both in <i>Apc^Min ^/+</i> mice and azoxymethane-treated mice, and reduced survival in <i>Apc^Min</i> ^/+ 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 <i>Map9</i> knockout <i>Apc^Min</i> ^/+ mice. In patients with colorectal cancer, <i>MAP9</i> was frequently silenced and its downregulation was associated with poor survival. 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.