| First Author | Kwon M | Year | 2021 |
| Journal | Cancer Res | Volume | 81 |
| Issue | 21 | Pages | 5523-5539 |
| PubMed ID | 34417201 | Mgi Jnum | J:312351 |
| Mgi Id | MGI:6784134 | Doi | 10.1158/0008-5472.CAN-21-0897 |
| Citation | Kwon M, et al. (2021) FILIP1L loss is a driver of aggressive mucinous colorectal adenocarcinoma and mediates cytokinesis defects through PFDN1. Cancer Res |
| abstractText | Aneuploid mucinous colorectal adenocarcinoma (MAC) is an aggressive subtype of colorectal cancer with poor prognosis. The tumorigenic mechanisms in aneuploid MAC are currently unknown. Here we show that downregulation of Filamin A interacting protein 1-like (FILIP1L) is a driver of MAC. Loss of FILIP1L increased xenograft growth, and, in colon-specific knockout mice, induced colonic epithelial hyperplasia and mucin secretion. The molecular chaperone prefoldin 1 (PFDN1) was identified as a novel binding partner of FILIP1L at the centrosomes throughout mitosis. FILIP1L was required for proper centrosomal localization of PFDN1 and regulated proteasome-dependent degradation of PFDN1. Importantly, increased PFDN1, caused by downregulation of FILIP1L, drove multi-nucleation and cytokinesis defects in vitro and in vivo, which were confirmed by time-lapse imaging and 3D cultures of normal epithelial cells. Overall, these findings suggest that downregulation of FILIP1L and subsequent upregulation of PFDN1 is a driver of the unique neoplastic characteristics in aggressive aneuploid MAC. |
