Background

Upper tract urothelial carcinoma, or UTUC, is a rare cancer. It makes up about 5–10% of cancers that start in the lining of the urinary tract. Because it is uncommon, proven treatments are limited. Many patients need surgery to remove the kidney and ureter, and the cancer can still return. The remaining kidney after surgery often does not have enough function for chemotherapy to be safe. 

What This Research Proposes to Address

This project will study genetic changes linked to UTUC, with a focus on a gene called KDM6A. The protein made from the KDM6A gene helps keep DNA properly packaged, so the right genes turn on or off in the cells that line the urinary tract, called the urothelium. There are no UTUC cell lines, so we will use bladder cancer cell lines as a model. Both cancers arise from the same urothelial lining and share similar behavior and genetic changes, which makes this a practical approach. We will define how loss of KDM6A changes DNA packaging, gene activity, and cell growth to promote urothelial cancer formation. We will also test whether epigenetic drugs can block these harmful programs. Epigenetic drugs change which genes are turned on or off without altering the DNA code. 

Why This Research Is Important

People with UTUC who relapse after surgery or cannot get chemotherapy have few options. By understanding how KDM6A drives this cancer and by identifying drug strategies that exploit these changes, this work aims to open the door to new, testable treatments and, ultimately, better outcomes for patients. 

Final Report Summary

KDM6A is a gene that is often mutated in upper tract urothelial carcinoma, or UTUC. The KDM6A gene makes a protein that helps pack DNA and controls which genes are read, so the right genes switch on or off at the right time. When this protein works properly, the cells that line the urinary tract, called the urothelium, keep their normal identity and growth. 

This project examines how KDM6A mutations affect UTUC. Because there are no UTUC-specific cell lines, the scientists ran experiments in bladder cancer cell lines. Both cancers start in the same urothelial lining and share similar behavior and gene changes, so bladder cancer cells are a relevant model for UTUC. Using a gene-editing tool, they disrupted KDM6A in these cells. After KDM6A was disrupted, DNA packaging and gene activity changed in harmful ways. Stress signals turned on, and the cells grew and divided faster. This gave the abnormal cells an advantage over healthy ones and may help start cancer. 

The group then tested drugs on cells lacking KDM6A. They were especially sensitive to an epigenetic drug. This type of drug changes which genes are turned on or off without changing the DNA code by blocking the cell’s reader proteins. One example is JQ1. These results suggest that epigenetic therapies could add to treatment options for urothelial cancers with KDM6A mutations, pending further study. 

In summary, the research helps explain how urothelial carcinomas begin and points to possible new treatment options for patients with this common genetic change. 

None Reported as of August 2025

None Reported as of August 2025

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