Losing expression of a certain isoform of the HSD17B4 gene makes men more likely to get castration-resistant prostate cancer (CRPC), a lethal form of the disease that does not respond to treatment, a new study shows. The study, “Loss of an Androgen-Inactivating and Isoform-Specific HSD17B4 Splice Form Enables Emergence of Castration-Resistant Prostate Cancer,” appeared in the journal Cell Reports. HSD17B4 produces proteins that inactivate androgens — the male hormones required for the growth of prostate cancer cells — helping to prevent aggressive disease. That alone should slow the disease's progression. Yet studies found that HSD17B4's expression was higher in men with advanced prostate cancer, suggesting that it was actually promoting disease progression instead. In an attempt to clarify whether HSD17B4 protects men from prostate cancer or promotes the disease, Cleveland Clinic researchers analyzed levels of HSD17B4 in patients with localized prostate cancer and CRPC, as well as in healthy controls. Because of a natural mechanism called splicing, HSD17B4 produces five different isoforms of the same protein. Each one comes from the same DNA code, but varies in amino acid sequence and physiological function. Researchers examined the levels of all isoforms and found that isoform 2 was specifically suppressed in the transition to CRPC. Additional experiments revealed that only this isoform effectively inactivated androgen and protected patients. While the total amount of HSD17B4 isoforms was higher in CRPC patients, most had lost isoform 2 expression, making them more prone to develop aggressive disease. This was confirmed in lab-grown cells lacking isoform 2. These cells had increased testosterone levels, which activated the androge