Revealing The Mechanism by Which Protein DUSP6 Promotes The Growth of Colorectal Cancer

Colorectal cancer is a type of cancer that begins in the colon (large intestine) or rectum, both of which are part of the digestive system. It usually starts as abnormal growths called polyps that form on the lining of the colon or rectum. Over time, some of these polyps may become cancerous if left untreated.

Colorectal cancer is one of the most common cancers in Singapore, with an average of about 2,540 cases per year, and is one of the leading causes of cancer death in Singapore. It is the third most common cancer worldwide, accounting for about 10% of cancer cases, according to the World Health Organization (WHO). Problems such as cancer recurrence and the development of drug resistance pose major challenges to colorectal cancer treatment, highlighting the need for new treatment approaches.

In a new study, researchers from the National University of Singapore Medical School have made a discovery that could change the way colorectal cancer is treated. They revealed that a molecule called Dual-Specificity Phosphatase 6 (DUSP6) plays an important role in helping colorectal cancer grow. The relevant research results were recently published in the journal Nature Communications, with the title of the paper "DUSP6 regulates Notch1 signaling in colorectal cancer".

The colorectal cancer cells tested in this study with higher DUSP6 levels proliferated about 40% more than those with lower DUSP6 levels. In colorectal cancer patients, increased DUSP6 content was associated with worse prognosis and decreased survival compared with patients with lower DUSP6 levels (p value = 0.029).

DUSP6 acts like a "turn off" of a specific signaling pathway within the cell. Its main function is to control the ERK1/2 MAPK pathway, which is important for cell growth, survival and repair. Under normal circumstances, DUSP6 inactivates ERK1/2, preventing cells from overgrowth or signaling. In some cancers, such as lung and skin cancers, DUSP6 acts as a tumor suppressor, helping to stop the growth of the cancer. However, in other cancers, such as colorectal cancer, DUSP6 has the opposite effect and promotes tumor growth.

"Higher levels of DUSP6 are found in colorectal cancer tumors, which helps cancer cells grow faster, spread more easily, and lead to worse prognosis for patients," said Zhang Yongliang, an associate professor in the Department of Microbiology and Immunology at the National University of Singapore Medical School and the corresponding author of the paper. "This unexpected role highlights why DUSP6 is now being considered as a possible target for the development of new treatments. Our study not only explains why some colon cancers are so aggressive, but also provides us with a clear target for the development of new treatments."

The new study found that DUSP6 protects cancer cells by inhibiting a process that usually destroys a key growth protein called Notch1. The Notch1 protein acts like a cell communicator, helping cells decide what to do, such as grow, divide, or assume a specific role. Notch1 is part of the Notch signaling pathway, which is critical in early development and maintaining healthy tissues. Notch1 becomes active when it interacts with specific proteins on the surface of neighboring cells. This triggers a series of "cuts" of this protein, releasing the intracellular domain (NICD) of Notch1.

Figure 1. Induced expression of DUSP6 promotes CRC growth and loss of DUSP6 in mice resulted in reduced colonic tumour development. (Png C W, et al., 2024)

NICD travels to the cell nucleus, where it switches on genes that drive cell growth, division and survival. When Notch1 is overactive or stabilized, it causes uncontrolled cell growth and can lead to cancer. In colorectal cancer, high levels of active Notch1 are associated with a poorer prognosis because it drives tumor growth and helps cancer cells survive longer. To control Notch1's activity, it must be phosphorylated (marked for subsequent destruction) and broken down by the cell's "recycling system". If this balance is disrupted, Notch1 may remain active for too long and promote cancer growth.

Associate Professor Veronique Angeli from the Department of Microbiology and Immunology at the National University of Singapore Medical School added, "Put simply, DUSP6 acts like a protector/controller of Notch1, preventing it from being broken down and keeping it active longer than it should be. This leads to increased tumor cell growth, faster spread of cancer cells and worse survival outcomes for colorectal cancer patients."

By blocking DUSP6, the possibility of developing new treatments for colorectal cancer could be realized. In laboratory models, the authors were able to significantly slow tumor growth by blocking this protein. High levels of DUSP6 are associated with worse survival, so it could also be used to predict the aggressiveness of a patient's cancer. While this study focused on colorectal cancer, the findings may also apply to other cancers where DUSP6 plays a role. They will study to further understand the pathogenesis of colorectal cancer and develop DUSP6-targeted therapies to treat this cancer to improve patient health outcomes.