Scientists at the University of North Carolina at Chapel Hill have identified a previously unknown function for the tumor suppressor gene SETD2. This gene, which is frequently mutated in clear cell renal cell carcinoma (ccRCC)—the most common form of kidney cancer—was found to play an important role in maintaining nuclear structure during cell division.
SETD2 has long been recognized for its role in modifying proteins that regulate gene expression and DNA repair. However, Brian Strahl, PhD, professor in the Department of Biochemistry and Biophysics and associate dean for basic research at the UNC School of Medicine, along with Abid Khan, PhD, discovered that SETD2 also helps preserve the shape and integrity of the nucleus within cells.
“Loss of SETD2 is one of the earliest events in kidney cancer development,” said Strahl. “What we found is that SETD2 has a separate function that’s essential for keeping the nucleus—and therefore the genome—intact.”
Their findings were published in Nature Cell Biology. The study shows that SETD2 assists with forming a protein scaffold called the nuclear lamina inside the nucleus. Without SETD2, this scaffold becomes distorted, leading to abnormal nuclear shapes and instability in genetic material—both considered hallmarks of cancer cells.
The research team focused on how these changes relate to ccRCC. In this type of cancer, deletion of part of a chromosome containing one copy of SETD2 often occurs early in disease development. While previous studies had examined its roles related to gene expression and DNA repair, this study revealed that during mitosis—the process where cells divide—SETD2 stabilizes nuclear structure by helping organize components responsible for dismantling and reassembling the nuclear envelope.
“What we found was a complete surprise,” said Khan. “For more than two decades, SETD2 has been studied for its enzymatic role. The idea that SETD2 could play a role in nuclear envelope breakdown was unimaginable and represents a paradigm shift in our understanding of this protein’s function in the cell.”
The researchers tested their findings using patient-derived ccRCC cells missing one copy of SETD2. They observed pronounced nuclear deformities associated with loss of this gene. When they reintroduced functional SETD2 into these cancer cells, normal nuclear shape was restored and tumor growth slowed.
“This finding is significant,” said Khan. “The ability to reverse nuclear deformities and slow cancer growth by adding SETD2 back in these patient cells suggests that we have uncovered a key mechanism through which SETD2 acts as a tumor suppressor.”
The implications may extend beyond kidney cancer; mutations or deletions affecting SETD2 are also seen in colorectal, prostate, and pancreatic cancers. Researchers believe this newly discovered structural function could represent a vulnerability across several types of tumors.
“This is an entirely new way of thinking about how loss of chromatin regulators contributes to cancer,” Strahl added. “SETD2 was hiding this critical function in plain sight—and now that we’ve uncovered it, the therapeutic possibilities are wide open.”
