The Role of Menin in Cancer and Tumor Development

Cancer News: Cancer research has taken a new turn with exciting discoveries regarding the role of a protein known as menin. A recent study by researchers from the Perelman School of Medicine at the University of Pennsylvania-USA delves deep into how this protein can both suppress and promote tumors, depending on the type of cancer. This Cancer News report covers the key findings of the study, providing insight into how menin interacts with various cancers and how it could lead to innovative treatments in the future.


The Role of Menin in Cancer and Tumor Development

What is Menin?
Menin is a protein encoded by the MEN1 gene, which primarily functions as a nuclear scaffold protein, interacting with multiple other proteins to regulate gene expression. This protein plays a unique role in cancer biology. Depending on the type of cancer, menin can either act as a tumor suppressor or a tumor promoter. While it is well-known for suppressing neuroendocrine tumors, such as those in patients with multiple endocrine neoplasia type 1 (MEN1) syndrome, recent findings indicate that menin also helps in suppressing cancers like pancreatic ductal adenocarcinoma, cholangiocarcinoma, and melanoma. On the other hand, menin can act as a promoter in leukemia, colorectal cancer, and some gynecological cancers.
 
How Menin Acts Differently in Various Cancers
Menin's role in cancer is highly tissue-specific. In some cancers, such as neuroendocrine tumors, menin serves as a powerful tumor suppressor. Loss of function of the MEN1 gene has been linked to the growth of these tumors. For example, in pancreatic neuroendocrine tumors (pNETs), menin controls the cell cycle by regulating the expression of cell cycle inhibitors. Without menin, pNET cells grow unchecked, leading to tumor formation. The researchers, based at the University of Pennsylvania, found that menin not only helps prevent the formation of pNETs but also plays a significant role in maintaining the stability of DNA, which further reduces the likelihood of cancerous cell growth.
 
Conversely, in leukemia, menin behaves quite differently. It partners with other proteins, such as the mixed-lineage leukemia (MLL) fusion proteins, to promote tumor growth. By interacting with MLL, menin helps activate genes that drive the proliferation of leukemia cells. Menin’s role in MLL-rearranged leukemia has been the subject of extensive study, and scientists believe that inhibiting this interaction could be a key to stopping the growth of leukemia.
 
Study Highlights: Menin as Both a Suppressor and Promoter
The research focuses on menin's dual role in different cancers. For example, in some solid tumors like lung adenocarcinoma and melanoma, menin serves as a suppressor. It prevents tumor formation by regulating cell proliferation and maintaining genetic stability. In these cases, the absence of menin allows cells to grow uncontrollably, which leads to tumor formation.
 
In other types of cancers, such as leukemia and colorectal cancer, menin acts as a tumor promoter. The protein ai ds in the activation of oncogenes (genes that can transform a cell into a tumor cell) through its interactions with proteins like MLL and PSIP1. These interactions disrupt normal cell regulation, allowing cancerous cells to thrive.
 
Menin can play both of these roles depending on the tissue type. For example, in breast and prostate cancers, menin's role varies based on hormone receptor status, and the protein can either suppress or promote tumor growth. Additionally, in hepatocellular carcinoma (HCC), some studies suggest menin acts as a tumor promoter, while others indicate a tumor-suppressive role.
 
Menin’s Role in Neuroendocrine Tumors
Neuroendocrine tumors (NETs) are a key area where menin’s tumor-suppressive abilities shine. Individuals with MEN1 syndrome, a condition caused by mutations in the MEN1 gene, are predisposed to developing NETs. In the endocrine pancreas, menin inhibits cell cycle progression by promoting the expression of inhibitors like p27 and p18. Without menin, these protective mechanisms are lost, leading to uncontrolled cell growth.
 
In pancreatic NETs, menin also maintains DNA integrity and promotes DNA repair. Loss of menin in pancreatic cells leads to genetic instability, which increases the likelihood of cancerous mutations. This discovery highlights the importance of menin in preventing the development of neuroendocrine tumors, offering hope for therapies that could restore its function in MEN1 patients.
 
Promoting Tumor Growth in Leukemia
Leukemia is one of the few cancers where menin functions primarily as a tumor promoter. The study team discovered that menin's interaction with MLL fusion proteins is essential for maintaining leukemia cells. By binding to MLL fusion proteins, menin activates the transcription of HOX genes, which are crucial for the proliferation of leukemia cells.
 
The study also explores the potential of small molecule inhibitors that target menin’s interaction with MLL. These inhibitors have shown promise in preclinical trials, reducing the growth of leukemia cells by disrupting the menin-MLL interaction. This opens up new possibilities for treating MLL-rearranged and NPM1 mutant leukemias, which are highly aggressive and difficult to treat with conventional therapies.
 
Therapeutic Potential of Menin Inhibitors
One of the most exciting aspects of this research is the potential for new cancer therapies that target menin. Small molecule inhibitors, known as menin inhibitors, have shown great promise in treating cancers where menin acts as a tumor promoter. In leukemia, these inhibitors block the interaction between menin and MLL fusion proteins, preventing the activation of oncogenes that drive cancer growth.
 
Clinical trials for menin inhibitors, such as SNDX-5613, are currently underway. Early results are promising, showing that these drugs can reduce leukemia cell growth and improve survival rates. These findings offer hope for patients with cancers driven by menin, particularly those with MLL-rearranged leukemia.

In contrast, therapies that restore menin’s tumor-suppressive function may be beneficial for cancers like pNETs, where the loss of menin drives tumor growth. Research into menin’s role in maintaining DNA integrity and controlling the cell cycle could lead to treatments that slow or prevent the progression of neuroendocrine tumors.
 
Conclusion: A Protein with Dual Roles in Cancer
The study of menin provides new insight into how cancer develops and offers hope for more effective treatments. Menin’s ability to act as both a tumor suppressor and a promoter makes it a unique target for cancer therapies. By inhibiting menin in cancers like leukemia and restoring its function in cancers like pNETs, researchers hope to develop treatments that are more precise and effective.
 
The dual role of menin highlights the complexity of cancer and the need for personalized approaches to treatment. While menin inhibitors show great promise in leukemia, restoring menin’s tumor-suppressive function could be key to treating neuroendocrine tumors and other cancers. As research continues, menin may prove to be a crucial player in the fight against cancer.
 
The study findings were published in the peer-reviewed journal: Genes.
https://www.mdpi.com/2073-4425/15/9/1231
 
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