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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA190415-01
Application #
8797489
Study Section
Cancer Molecular Pathobiology Study Section (CAMP)
Program Officer
Mietz, Judy
Project Start
2015-04-06
Project End
2020-03-31
Budget Start
2015-04-06
Budget End
2016-03-31
Support Year
1
Fiscal Year
2015
Total Cost
$366,000
Indirect Cost
$137,250
Name
University of Pennsylvania
Department
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Zhang, Lin; Peng, Dan; Sood, Anil K et al. (2018) Shedding Light on the Dark Cancer Genomes: Long Noncoding RNAs as Novel Biomarkers and Potential Therapeutic Targets for Cancer. Mol Cancer Ther 17:1816-1823
Wang, Yanling; Xu, Haineng; Liu, Tianrun et al. (2018) Temporal DNA-PK activation drives genomic instability and therapy resistance in glioma stem cells. JCI Insight 3:
Yuan, Jiao; Hu, Zhongyi; Mahal, Brandon A et al. (2018) Integrated Analysis of Genetic Ancestry and Genomic Alterations across Cancers. Cancer Cell 34:549-560.e9
Liu, Tianrun; Ma, Wenjuan; Xu, Haineng et al. (2018) PDGF-mediated mesenchymal transformation renders endothelial resistance to anti-VEGF treatment in glioblastoma. Nat Commun 9:3439
Hu, Xiaowen; Sood, Anil K; Dang, Chi V et al. (2018) The role of long noncoding RNAs in cancer: the dark matter matters. Curr Opin Genet Dev 48:8-15
Lu, Yunqi; Hu, Zhongyi; Mangala, Lingegowda S et al. (2018) MYC Targeted Long Noncoding RNA DANCR Promotes Cancer in Part by Reducing p21 Levels. Cancer Res 78:64-74
Lin, Xiaojuan; Shen, Jianfeng; Dan Peng et al. (2018) RNA-binding protein LIN28B inhibits apoptosis through regulation of the AKT2/FOXO3A/BIM axis in ovarian cancer cells. Signal Transduct Target Ther 3:23
Yang, Lu; Zhang, Youyou; Shan, Weiwei et al. (2017) Repression of BET activity sensitizes homologous recombination-proficient cancers to PARP inhibition. Sci Transl Med 9:
Zhang, Youyou; Dang, Chi V; Zhang, Lin (2017) BETting on combination to overcome PARPi resistance. Oncotarget 8:84630-84631
Zhang, Dongmei; Zhang, Gao; Hu, Xiaowen et al. (2017) Oncogenic RAS Regulates Long Noncoding RNA Orilnc1 in Human Cancer. Cancer Res 77:3745-3757

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