Study finds abnormal alternative RNA splicing patterns in aggressive prostate cancer

Aggressive forms of prostate cancer don't act the way they should, hanging on to genetic materials called introns that should be thrown away, a new six-year study led by Dean Tang, Ph.D., and Song Liu, Ph.D., of Roswell Park Comprehensive Cancer Center has revealed. The team's discovery, reported in a new article in Nature Communications, could lead to treatment that targets abnormal RNA splicing prevalent in advanced tumors -; and to the ability to distinguish more aggressive prostate cancers from those that will progress more slowly.

The team set out to learn how prostate cancer cells differ from normal, healthy prostate cells, in particular how those cancerous cells transcribe their genes. The researchers focused on alternative splicing, the process by which a DNA sequence is transcribed into RNA forms in an abnormal manner compared to healthy cells, resulting in tumors.

Cancer cells are obviously bad cells, but they may also have abnormal, what we would call 'deregulated' molecular and biological properties that may make them vulnerable. We wanted to explore whether those vulnerabilities could be identified and exploited."

Dr. Dean Tang, Chair of Pharmacology and Therapeutics at Roswell Park Comprehensive Cancer Center and senior author

The team made several important discoveries, each with important translational and clinical implications. First, they found that as prostate cancer progresses and becomes more aggressive, gene splicing also becomes more unregulated, meaning the RNA splicing pattern is increasingly abnormal. Secondly, very aggressive cancer cells are more likely to splice RNA in abnormal fashion. Third, they found that these aggressive prostate cancer types are more frequently enriched by retaining introns, segments of genetic code that do not become proteins. These observations are consistent with emerging data in other cancer types.

"We found, surprisingly, that when prostate cancer cells become more aggressive, they have more genes that retain the introns in their messenger RNA, or mRNA," notes Dr. Liu, Vice Chair of Roswell Park's Department of Biostatistics and Bioinformatics. "We have observed this retention and also noted that retention of introns is more pronounced in advanced tumors."

Currently, clinicians do not have reliable methods for determining whether a prostate tumor is indolent, not requiring immediate treatment, or is dangerously aggressive. The abnormal alternative RNA splicing patterns in aggressive prostate cancer suggest that these splicing processes could be developed into biomarkers that could be used to distinguish tumors that develop slowly from those that will be more aggressive.

The findings also reveal that aggressive prostate cancers might be more susceptible than indolent tumors to chemical inhibitors of the splicing machinery and that intron retention can be exploited for development of immunotherapies for treatment-resistant and aggressive tumors. The team plans further projects to pursue these implications.