ddn Cancer Research News Exclusive: Jewels from junk

LA JOLLA, Calif.—The decoding of the human genome unlocked awealth of information about human biology, including the discovery that lessthan 2 percent of our genome actually codes for proteins. Following the HumanGenome Project, most research attention was focused on the coding DNA,dismissing the "junk" or non-coding DNA as superfluous. But more recentresearch, including the Encyclopedia of DNA Elements (ENCODE) project, hasshown that even junk DNA plays significant roles in our biological functions.

Among that all that "junk" are small stretches of DNA knownas "pseudogenes," which boast sequences nearly identical to those of standardgenes yet are non-coding, and according to a new study from The ScrippsResearch Institute, some of those pseudogenes regulate the activity of thephosphatase and tensin homolog (PTEN), a cancer-related gene.

The study was lead by Scripps scientist Kevin Morris, Ph.D.,in collaboration with scientists at the Karolinska Institutet in Stockholm,Sweden, and the University of New South Wales in Sydney, Australia.

The researchers demonstrated that pseudogenes are capable ofinfluencing PTEN's activity, an exciting discovery considering the gene'sidentification as a tumor suppressor gene. Though pseudogenes don't code forproteins, this latest work by Morris and colleagues has revealed that thegenetic sequences exert control over the activity of various genes. Pseudogenesthat have sequences in common with PTEN can regulate the gene by eithersuppressing the "promoter" for PTEN and preventing it from being expressed, orsoaking up PTEN-targeted regulatory microRNAs that affect the gene after itsgenetic transcripts are expressed.

According to Morris, two other papers "on pseudogenesregulating protein-coding genes" were published previous to this most recent NatureStructural & Molecular Biology study,one of which was from Morris' group. One paper focused on PTENpg1 sense,showing that "the PTEN pseudogene 1 (PTENpg1) controls micro RNA targeting ofthe PTEN protein expression, e.g. transient translational control of proteinexpression in the cytoplasm." The other paper from Morris' group showed thatOct4—octamer-binding transcription factor 4, which plays a pivotal role in thedifferentiation of embryonic stem cells—is controlled by a pseudogene in termsof epigenetics and transcription.

Pseudogenes, says Morris, can be targeted directly by usingantisense RNAs, oligos or RNAi, and it is possible to control both of PTEN'sfunctions.

"We can control both aspects of the pseudogenes' effects,and both are equally easy to modulate, but the targeting the transpirationalregulatory PTENpg1 antisense RNA alpha variant is the way to go, as it leads toactivation of PTEN transcription, e.g., we turn up PTEN," Morris explains. "Thetargeting of the PTENpg1 sense only transiently affects PTEN. In brain tumorswhere PTEN is suppressed, stable activation can significantly prolong life ifnot double the survival following removal of the tumor."

Morris cautions that targeting pseudogenes as a therapeuticapproach has some technical issues, primarily in the sense that developing adrug that can target pseudogenes would have to be delivered directly to thecells where it is needed without affecting healthy tissues. Even so,therapeutics that could activate PTEN could make waves in several types ofcancer, says Morris, including glioblastomas and melanomas, as well as strokeand head injuries.

Morris and his colleagues will be continuing this researchin several directions, he adds, including such fields as HIV latency, cysticfibrosis and autism, in addition to cancer.

"The coolest thing of this work is it's an entirelyunrecognized mode of action that is controlling gene expression and epigeneticheritability, really a far-out paradigm shift that now allows us to selectivelyactivate gene expression," Morris concludes.

The study, "A pseudogene long non-coding RNA networkregulates PTEN transcription and translation in human cells," appeared in theFeb. 24 issue of Nature Structural & Molecular Biology, and was supported by the National Institute ofAllergy and Infectious Disease, the National Cancer Institute, the SwedishChildhood Cancer Foundation, the Swedish Cancer Society, RadiumhemmetsForskningsfonder, the Karolinska Institutet Ph.D. support program,Vetenskapsrådet and the Erik and Edith Fernstrom Foundation for MedicalResearch.