The Oncosuppressive Properties of KCTD1: Its Role in Cell Growth and Mobility.

Simple Summary: Members of the KCTD protein family play major roles in numerous physiopathological functions. Although they are traditionally considered to be involved in neurological and neurodevelopmental processes, there is increasing evidence of their roles as either oncogenic or oncosuppressor factors. Here, we show that KCTD1 has an active role in modulating the stemness and mobility of colon cancer cell lines by affecting the WNT/β-catenin signalling pathway. These findings, which are also supported by analyses of The Cancer Genome Atlas (TCGA) database, provide evidence of the role of KCTD1 as an oncosuppressor. The KCTD protein family is traditionally regarded as proteins that play key roles in neurological physiopathology. However, new studies are increasingly demonstrating their involvement in many other biological processes, including cancers. This is particularly evident for KCTD proteins not involved in protein ubiquitination and degradation, such as KCTD1. We explored the role of KCTD1 in colorectal cancer by knocking down this protein in the human colon adenocarcinoma cell line, SW480. We re-assessed its ability to downregulate β-catenin, a central actor in the WNT/β-catenin signalling pathway. Interestingly, opposite effects are observed when the protein is upregulated in CACO2 colorectal cancer cells. Moreover, interrogation of the TCGA database indicates that KCTD1 downregulation is associated with β-catenin overexpression in colorectal cancer patients. Indeed, knocking down KCTD1 in SW480 cells led to a significant increase in their motility and stemness, two important tumorigenesis traits, suggesting an oncosuppressor role for KCTD1. It is worth noting that similar effects are induced on colorectal cancer cells by the misregulation of KCTD12, a protein that is distantly related to KCTD1. The presented results further expand the spectrum of KCTD1 involvement in apparently unrelated physiopathological processes. The similar effects produced on colorectal cancer cell lines by KCTD1 and KCTD12 suggest novel, previously unreported analogous activities among members of the KCTD protein family. [ABSTRACT FROM AUTHOR]