New Research Links Gene Variant to Deadly Prostate Cancer

Cleveland Clinic researchers have confirmed for the first time a mechanistic link between an isoform of the gene HSD17B4 and deadly prostate cancer.

“Our research shows that men who lack a certain subtype of HSD17B4 may be more susceptible to castration-resistant prostate cancer (CRPC),” says medical oncologist and physician-researcher Nima Sharifi, MD, of Cleveland Clinic Lerner Research Institute Department of Cancer Biology, Glickman Urological & Kidney Institute and Cleveland Clinic Taussig Cancer Institute, who led the study.

Dr. Sharifi and colleagues build upon their earlier seminal work in which they discovered that when altered, a related gene, HS, enables prostate tumors to evade treatment and proliferate. They went on to show that the presence of this gene variant changes treatment outcomes and overall survival in men.The study, published in Cell Reports, was supported by awards or grants from Howard Hughes Medical Institute, Prostate Cancer Foundation, American Cancer Society and the National Cancer Institute.

Previous research showed that HSD17B4 encodes enzymes that inactivate androgens. Since androgens are essential for prostate cancer growth, inactivating them should in theory prevent cancer advancement. But these enzymes have also been observed to be more abundant in advanced prostate cancer.

It has therefore remained unclear whether the enzymes promote or suppress prostate cancer. The current study shows that the enzymes in fact suppress prostate cancer.

Androgen deprivation therapy

Androgen deprivation therapy (ADT), or chemical castration, blocks cells’ supply of androgens. While ADT is successful early on, it eventually fails, allowing prostate cancer to progress to the lethal CRPC phase of the disease.

To determine HSD17B4’s role in the transition to CRPC, Dr. Sharifi’s team compared and analyzed its expression in tissue from patients with healthy prostates, localized prostate cancer and CRPC. They found that HSD17B4 expression levels were relatively similar in benign and local prostate cancer tissue, but significantly reduced in CRPC tissue, suggesting that HSD17B4 does play a role in preventing the progression to CRPC.

Role of isoforms

Castration-resistant prostate cancer (CRPC) is dependent on metabolic processes that enable sustained tumor androgens, which generally require androgen-synthesizing enzymes. This research shows that a single androgen inactivation enzyme splice form is lost in CRPC and encodes the only enzyme that otherwise blocks androgen action and lethal disease.

There are different splice variants, or isoforms, of the HSD17B4 gene. Isoforms do not vary in DNA sequence or genetic code; rather, their translated amino acids are organized differently, which leads to variations in physiological function. HSD17B4 has five distinct isoforms.

Through a series of analyses, the researchers found that only one specific isoform of HSD17B4 — isoform 2 — enzymatically inactivated androgens and prevented tumor growth. It is expressed during the early phases of prostate cancer, but is lost or suppressed in CRPC.

To validate these findings, the team transplanted CRPC tumor cells into a preclinical mouse model of prostate cancer and genetically silenced HSD17B4. The prostate cancer tumors grew and spread much quicker in the HSD17B4-negative group compared to the control group. Taken together, these findings suggest that isoform 2 prevents prostate cancer cells from developing and using their own androgen supply. In the absence of isoform 2, prostate cancer evades ADT and progresses to CRPC.

Future studies

“Currently men with CRPC are not curable, leading to an urgent need for new therapeutic approaches,” comments Eric Klein, MD, Chairman, Glickman Urological & Kidney Institute. “Like the prior work on HSDB3, this study adds further insight into the molecular mechanisms of progression from hormone-sensitive to castration-resistant disease, and provides new avenues to explore to help prevent this from happening.”

Additional research will be important to elucidate how HSD17B4 becomes silenced in CRPC and whether it may one day be used as a biomarker for patients at risk of dying from prostate cancer.

Postdoctoral fellow Hyun-Kyung Ko, PhD, Department of Cancer Biology, is first author on the study. Dr. Sharifi holds the Kendrick Family Chair for Prostate Cancer Research at Cleveland Clinic and co-directs the Cleveland Clinic Center for Excellence in Prostate Cancer Research. He has received numerous national awards for his work in uncovering the link between HSD3B1 and CRPC, including the Clinical Research Forum’s Top 10 Clinical Research Achievement Award in 2017.