Cancer is a genetic disease involving multi-step changes in the genome. The human genome contains ~25,000 protein-coding genes, representing less than 2% of the total genome, whereas up to 70% of the human genome is transcribed into RNA, yielding many thousands of non-coding RNAs. The recent discovery of non-coding RNAs, including small non-coding RNAs such as microRNA, has dramatically altered our understanding of cancer. However, research on long non-coding transcripts is still in its infancy. Long non-coding RNAs (lncRNAs) are operationally defined as RNA transcripts larger than 200 nt that do not appear to have protein-coding potential. Rapidly accumulating evidence indicates that lncRNA is involved in the initiation and progression of cancer. A novel oncogenic lncRNA, FAL1 (Focal Amplified lncRNA 1), has recently been identified by the PI's laboratory. Our preliminary data indicate that: amplification and high expression of FAL1 are correlated with poorer outcomes in cancer; FAL1 RNA associates with the epigenetic repressor BMI1, regulating its stability; knockdown of FAL1 increases the transcription of a number of genes, including CDKN1A; the oncogenicity of FAL1 is partially attributable to its repression of p21 expression; and FAL1-specific small interfering RNAs significantly inhibit tumor growth in vivo. Therefore, we hypothesize that the novel oncogenic lncRNA FAL1 epigenetically regulates multiple cancer-associated pathways via its interaction with BMI1, and that the investigation of the function of FAL1 may provide novel biomarkers and therapeutic targets for patients with cancer. We will test this hypothesis through the following specific aims:
Specific Aim 1. Characterize the molecular mechanisms by which FAL1 regulates BMI1 stability.
Specific Aim 2. Identify the molecular network epigenetically regulated by FAL1/BMI1 in cancer cells.
Specific Aim 3. Examine the cellular functions of FAL1 in cancer initiation and progression.

Public Health Relevance

Cancer is a genetic disease involving multi-step changes in the genome. Up to 70% of the human genome is transcribed into RNA, yielding many thousands of long non-coding RNAs (lncRNAs). We will conduct functional studies on the role of lncRNA in tumor initiation and progression with the intent to further understand the alterations of cancer genomes, and identify novel therapeutic targets and strategies.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Cancer Molecular Pathobiology Study Section (CAMP)
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Mietz, Judy
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University of Pennsylvania
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