The Wnt/beta-catenin signaling pathway regulates stem cell renewal and cell proliferation by controlling DNA transcription, and its abnormal activation plays a role in many cancers. Now, scientists at the University of Toronto have identified a protein related to the pathway they say drives many colorectal cancers.
The protein is called Importin-11. Its coding gene, IPO11, belongs to the Importin-beta family, which mediates trafficking between the cell nucleus and cytoplasm for different cellular functions. In Importin-11’s case, it transports beta-catenin into the nucleus of colon cancer cells, where it can lead to cell growth, according to the team’ findings, published in the Journal of Cell Biology.
About 80% of colorectal cancers are caused by loss-of-function mutations to a gene called APC. Normally, APC helps degrade beta-catenin. Without it, beta-catenin can accumulate in the nucleus, further activating several genes that promote the growth of colorectal tumors.
While scientists know mutations in APC cause beta-catenin nuclear buildup in colorectal cancer, they don’t fully understand how the protein enters the cell nucleus.
“Because the molecular mechanisms underlying beta-catenin nuclear transport remain unclear, we set out to identify genes required for continuous beta-catenin activity in colorectal cancer cells harboring APC mutations,” Stephane Angers, the study’s corresponding author, said in a statement.
To do that, Angers’ team developed a CRISPR-Cas9 gene editing screening tool. As expected, the researchers found that beta-catenin’s coding gene CTNNB1 and its known co-transcriptional activator BCL9L were the first- and third-highest ranked genes in a genome-wide screen of APC-mutated colorectal cancer.
But a gene with no previous link to beta-catenin-mediated signaling emerged as the second-highest related gene. That was IPO11.
After a series of tests, Angers and colleagues confirmed that IPO11 is required for beta-catenin nuclear import. Specifically, Importin-11 binds to beta-catenin and guides it into the cell nucleus of colorectal cancer cells with APC mutations, the team noted, and silencing it strongly inhibited the nuclear localization of beta-catenin.
To confirm the functional importance of Importin-11, the team removed the protein. That led to a reduction of a tumor colony in lab dishes and slowed the growth of patient-derived cancer organoids.
Because of its role in cell differentiation, the Wnt/beta-catenin pathway has been a target for other cancer researches. Boston-based startup FogPharma has a beta-catenin inhibitor as its lead program. The biotech is designing polypeptides, which are small proteins, to target previously undruggable cancers, according to the company.
Scientists from New York University previously designed similar molecules that were a cross between large biologics and small molecules. Called peptoids, the drugs targeted Wnt and the interaction between beta-catenin and T-cell factor. In zebrafish, the lead compound showed promise as a potential prostate cancer treatment.
Blocking Importin-11 from shuttling beta-catenin into the nucleus could serve as a new strategy for treating colorectal cancer, the University of Toronto team argued. Further understanding of the process may guide the development of new therapies that reduce the growth of APC-mutated colorectal cancer.