Understanding The Regulatory Roles of lncRNA

Pavel Sumazin, PhD is assistant professor of pediatrics at Baylor College of Medicine and director of the Bioinformatics Core Laboratory and a member of the Cancer Genetics and Genomics Program and the Center for Precision Oncology, Texas Children’s Hospital, in Houston. Cancer Network spoke with Sumazin about his work on the regulatory roles of long noncoding RNA (lncRNA) in cancer.

Cancer Network: Can you start by explaining a little about the range of regulatory roles lncRNAs play in gene expression?

Dr. Sumazin: Most lncRNAs remain uncharacterized, and much of the current efforts still focus on their cataloging and profiling. While some estimates have the number of human lncRNAs at 40,000, only a dozen or so of the highest-expressed lncRNA species have been interrogated for function in human diseases and normal cells. These lncRNAs are known to regulate gene transcription by altering chromatin structure-the availability of regulatory regions and encoded genes to transcriptional machinery-or by directly targeting gene promoters and either activating or repressing other transcriptional factors. Some lncRNAs have been shown to target and either activate or inhibit the activity of transcription factors, while others target and modulate the activity of microRNAs, RNA-binding proteins, or the cell’s translational machinery. We, and others, have shown that increasing or inhibiting the expression of lncRNAs can dramatically alter the expression of key genes that play important roles in healthy cells and in cancers.

Cancer Network: Where have you focussed your efforts to understand lncRNA??

Dr. Sumazin: Given that little is known about the function of most lncRNAs, our efforts have been focused on understanding their regulatory roles-how they influence genes with known function in cancers. lncRNAs provide an opportunity for indirectly targeting known key cancer genes and pathways, and our efforts in recent years focused on identifying lncRNAs that are both preferentially expressed in tumors-these lncRNAs are not required for normal activity in mature tissues-and regulate key cancer genes and pathways.

Targeting these lncRNAs will block cancer pathways while having minimum effect on normal tissues. We’ve been studying how targeting such lncRNAs can help improve the efficacy of current cancer treatments, including radiation. We also study lncRNAs as predictors for the efficacy of therapies; we believe that lncRNAs can indicate which patients will benefit from radiation, and which patients are in danger for developing metastatic lesions and may require more intensive intervention.

Cancer Network: How has your team approached pan-cancer analysis of lncRNA regulatory interactions in tumor genomes?

Dr. Sumazin: In order to identify therapeutic-candidate lncRNAs it was important for us to both identify functional lncRNAs in cancer and to understand how these lncRNAs function. We built models for the activity of lncRNAs and identified lncRNAs that fit these models and that account for the dysregulation of cancer genes and pathways.

Our methodology was unique in that we not only showed that there is widespread regulation of cancer pathways by lncRNAs, but we identified hundreds of lncRNAs in each cancer type that may be targeted to influence cancer cells in a specific manner. Previous efforts suggested that lncRNAs may be important in cancer, but they focused on a specific cancer type or did not provide evidence for the function of these lncRNAs. We identified lncRNAs that target specific cancer genes and pathways in each cancer type, and we identified pan-cancer lncRNAs whose activity is common to many cancer types.

Cancer Network: What did you and your team find?

Dr. Sumazin: We found that lncRNA dysregulation, including dysregulation that is due to copy number alterations at their loci, can account for some of the missing genomic variability observed for cancer genes. After aggregating all our knowledge about cancer gene dysregulation, we are still unable to explain dramatic changes in the expression of key cancer genes in most cancers. Dysregulation of lncRNAs through amplifications and deletions at their loci-copy number alterations-accounts for a significant proportion of this unexplained dysregulation.

Cancer Network: What are the clinical and research implications of your team's findings? How might lncRNA roles in tumor cells’ proliferation pathways be targeted?

Dr. Sumazin: There are multiple targeting methods for lncRNAs. These include traditional, small-molecule based targeting, siRNA-based delivery, and small RNA and DNA-based delivery systems. We are working with multiple groups on delivery methods to target lncRNAs.