Bladder-cancer-associated mutations in RXRA activate peroxisome proliferator-activated receptors to drive urothelial proliferation

Abstract

RXRA regulates transcription as part of a heterodimer with 14 other nuclear receptors, including the peroxisome proliferator-activated receptors (PPARs). Analysis from TCGA raised the possibility that hyperactive PPAR signaling, either due to PPAR gamma gene amplification or RXRA hot-spot mutation (S427F/Y) drives 20–25% of human bladder cancers. Here, we characterize mutant RXRA, demonstrating it induces enhancer/promoter activity in the context of RXRA/PPAR heterodimers in human bladder cancer cells. Structure-function studies indicate that the RXRA substitution allosterically regulates the PPAR AF2 domain via an aromatic interaction with the terminal tyrosine found in PPARs. In mouse urothelial organoids, PPAR agonism is sufficient to drive growth-factor-independent growth in the context of concurrent tumor suppressor loss. Similarly, mutant RXRA stimulates growth-factor-independent growth of Trp53/Kdm6a null bladder organoids. Mutant RXRA-driven growth of urothelium is reversible by PPAR inhibition, supporting PPARs as targetable drivers of bladder cancer.

eLife digest

Bladder cancer is the sixth most common type of cancer in the United States. At the moment, treatment options for advanced bladder cancer are limited to chemotherapy and immunotherapy, both of which benefit only some patients. Many other types of cancer can be treated with drugs that are specific to genetic mutations found in those cancer cells, often making the treatments more efficient with fewer side effects.

Between 5–8% of people with bladder cancer have a mutation in the gene that produces a protein called RXRA. This protein partners with itself or with other proteins to control gene activity. However, it was not clear what mutant RXRA proteins do in bladder cancer cells.

Halstead et al. studied the RXRA mutation in human bladder cancer cells and “mini-bladders” grown in the laboratory from mouse bladder cells. Biochemical experiments showed that the mutant RXRA protein causes abnormally high activity in one group of its partner proteins, called peroxisome proliferator-activated receptors (PPARs). The PPARs, in turn, switch on genes that help cancer cells to grow and multiply. Computational simulations of the mutant RXRA binding to PPARs revealed, at a molecular level, how this activation occurs. Lastly, Halstead et al. used chemicals that block the activity of PPARs to stop the growth of cells in the mouse mini-bladders that contained the RXRA mutation.

These findings suggest that bladder cancer patients with the RXRA mutation may benefit from therapies that inhibit PPARs. Such therapies could also benefit the approximately 15–20% of people with bladder cancer who do not have the RXRA mutation but who do have over-active PPARs. Although there are chemicals that block the activity of PPARs, more research is needed to refine them before they can be used to treat cancer.