KCTD9 is a potential prognostic and therapeutic target for colorectal cancer

According to the recent GLOBOCAN, colorectal cancer (CRC) is estimated to have the third highest incidence and the second highest mortality rate of all cancers in 2020, based on data from the International Agency for Research on Cancer (IARC). A substantial proportion of colon cancer patients are discovered at advanced stages, and mortality is mostly connected with a high prevalence of metastases, particularly liver metastases, caused in part by direct circulation in the portal vein.

Early screening and enhanced management programs have improved patient prognosis dramatically, yet the demands of patients with progressing disease remain unfulfilled. To develop more effective biomarkers and therapeutic targets, a deeper knowledge of the molecular underpinnings of colorectal carcinogenesis and progression is required.

Recently, researchers from the University of Science and Technology of China published an article in Cell Death and Disease titled "KCTD9 inhibits the Wnt/β-catenin pathway by decreasing the level of β-catenin in colorectal cancer", which showed that KCTD9 inhibits the Wnt/β-catenin pathway to suppress the proliferation and metastasis of colorectal cancer cells.

CRC is the second leading cause of cancer death worldwide. However, the molecular mechanisms of CRC progression remain to be further investigated to improve patient prognosis. In this study, the investigators found that KCTD9, a member of the KCTD9 gene family, was commonly downregulated in colorectal cancer tissues and that KCTD9 expression was negatively correlated with clinical stage. Survival analysis showed that patients with low levels of KCTD9 expression had a poorer prognosis.

Functional study revealed that KCTD9 overexpression decreased colorectal cancer cell proliferation and metastasis, whereas KCTD9 knockdown increased colorectal cancer cell proliferation and metastasis. Regulation of KCTD9 expression in colorectal cancer cells by overexpression or knockdown revealed that KCTD9 expression favorably influenced β-linked protein degradation, resulting in Wnt signaling suppression and lower expression of Wnt pathway target genes.

Mechanistically, investigators found that KCTD9 was found to be associated with zinc transporter protein 9 (ZNT9), a coactivator of β-linked protein-mediated gene transcription. overexpression of the KCTD9 gene or knockdown of the ZNT9 gene increased ubiquitination and proteasomal degradation of β-linked proteins. In turn, KCTD9-ZNT9 interaction disrupts the interaction between β-linked protein and ZNT9, which leads to reduced expression of β-linked protein target genes and inhibition of Wnt signaling.

In summary, KCTD9 can be used as a potential target for determining the prognosis and treatment of colorectal cancer. In addition, based on the findings of this study, it would be valuable to investigate the expression status of KCTD9 in other cancer types, especially those known to be driven by abnormal Wnt signaling.

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