A new study led by scientists at the University of North Carolina at Chapel Hill reveals a surprising new role for the tumor suppressor gene, SETD2, which is frequently mutated in clear cell renal cell carcinoma (ccRCC)-the most common form of kidney cancer and one of the ten most common cancers in both men and women in the United States, according to the American Cancer Society.
While SETD2 is best known for chemically modifying proteins to regulate gene expression and DNA repair, UNC School of Medicine biochemists Brian Strahl, PhD, and Abid Khan, PhD, discovered that the enzyme also plays a crucial structural role in preserving the shape and integrity of the nucleus - part of the cell that stores DNA.
This latest finding offers fresh insights into SETD2's role in protecting the genome and suppressing tumor growth- and how loss of this crucial gene may be contributing to the development of kidney as well as other cancers.
Brian Strahl, PhD
"Loss of SETD2 is one of the earliest events in kidney cancer development," said senior author Strahl, professor in the Department of Biochemistry and Biophysics and associate dean for basic research at the UNC School of Medicine. "What we found is that SETD2 has a separate function that's essential for keeping the nucleus-and therefore the genome-intact."
The research, published in the journal Nature Cell Biology, reveals that SETD2 assists in the formation of a supportive protein scaffold that lines the inside of the nucleus. Without SETD2, the scaffold, termed the nuclear lamina, becomes distorted. This results in abnormal nuclear shapes, DNA breaks, and genome instability-all hallmarks of cancer cells.
SETD2 and the Cell Cycle
Clear cell renal cell carcinoma (ccRCC), the most common form of kidney cancer, is thought to start when part of a chromosome-containing one of two copies of the SETD2 gene-is deleted. Given this connection, and its well-established roles in gene expression and in the repair of broken DNA, SETD2 has been under the microscope of researchers for years.
Until now, however, scientists believed that SETD2's tumor-suppressing function was limited to its previously described functions in gene expression and DNA repair. But this new study reveals a surprising new twist: SETD2 is "moonlighting" during mitosis-the stage of the cell cycle when cells divide-to stabilize the structure of the nucleus thereby protecting the genome.
Normally, the nucleus remains intact throughout the life of a cell, safeguarding its genetic material.
But during mitosis, this nuclear structure must briefly break apart so that chromosomes can properly separate into two new daughter cells. The researchers discovered that SETD2 helps to organize this process by tethering the molecular machinery involved in dismantling the nuclear envelope.
Abid Khan, PhD
During mitosis, the enzyme assists in the temporary disassembly of the nuclear lamina-a mesh-like network of structural proteins (lamins) that underlies and supports the nuclear envelope. Once cell division is complete, lamin proteins snap back into their original scaffold, restoring the spherical shape of the nucleus that continues to protect the DNA within.
"What we found was a complete surprise," said Khan, a research associate in the Strahl Lab. "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."
Confirming SETD2's New Role in Kidney Cancer
With the new findings, researchers were then tasked with figuring out exactly how its newfound role ties into human disease and cancer development.
To test this, Khan and Strahl turned to ccRCCs, the most common type of kidney cancer where a copy of SETD2 is often lost. They found that in patient-derived ccRCC cells, the cancer-linked loss of SETD2 was already associated with striking nuclear deformities.
And when the researchers reintroduced a functional extra copy of SETD2 to the cancer cells, they made a remarkable discovery-the nuclei restored their spherical shapes 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."
Findings Can Apply to Other Cancers, Too
The implications extend beyond kidney cancer.
SETD2 mutations or deletions also occur in colorectal, prostate, and pancreatic cancers, suggesting this newly discovered structural function may represent a broader vulnerability in cancer biology.
"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."
