Epigenetic aberrations are a key driver of cancer pathogenesis. Long intergenic noncoding RNAs (lincRNAs) have emerged as a pervasive and important class of regulators that serve as the interface between DNA and chromatin modification machinery. The lincRNA HOTAIR is overexpressed in approximately a third of human breast carcinomas and is a powerful predictor of eventual metastasis and death. HOTAIR reprograms the breast cancer chromatin state to alter the positional identity of the cancer cells, enabling invasion and metastatic spread to distant organs. The long term goal of this project is to understand the mechanistic basis of lincRNA action in human cancers. First, using HOTAIR as a model system, we will address the structure-function relationship of a lincRNA and its oncogenic activities. Second, we will examine how HOTAIR targets specific genomic loci to relocalize Polycomb proteins. Third, we will determine whether HOTAIR may serve as a therapeutic target by testing its ongoing requirement during cancer progression. These experiments will provide key insights into how long noncoding RNAs may instigate cancer progression, and should pave the way for new cancer diagnostics and treatments in the future. !
Breast cancer is the second most common cause of cancer death for women in the United States. These deaths are most often caused by the spread of breast cancer to other sites of the body. A new type of genes, termed long intergenic noncoding RNA (lincRNA) has been found to be important to promote breast cancer progression by increasing metastasis. Research into how lincRNAs change gene activities in breast cancer will help to improve the risk assessment of breast cancer patients and identify targets for cancer therapy.
|Schmitt, Adam M; Garcia, Julia T; Hung, Tiffany et al. (2016) An inducible long noncoding RNA amplifies DNA damage signaling. Nat Genet 48:1370-1376|
|Schmitt, Adam M; Chang, Howard Y (2016) Long Noncoding RNAs in Cancer Pathways. Cancer Cell 29:452-63|
|Li, Lingjie; Chang, Howard Y (2014) Physiological roles of long noncoding RNAs: insight from knockout mice. Trends Cell Biol 24:594-602|
|Flynn, Ryan A; Chang, Howard Y (2014) Long noncoding RNAs in cell-fate programming and reprogramming. Cell Stem Cell 14:752-61|
|Batista, Pedro J; Molinie, Benoit; Wang, Jinkai et al. (2014) m(6)A RNA modification controls cell fate transition in mammalian embryonic stem cells. Cell Stem Cell 15:707-19|
|Zheng, Grace X Y; Do, Brian T; Webster, Dan E et al. (2014) Dicer-microRNA-Myc circuit promotes transcription of hundreds of long noncoding RNAs. Nat Struct Mol Biol 21:585-90|
|Quinn, Jeffrey J; Ilik, Ibrahim A; Qu, Kun et al. (2014) Revealing long noncoding RNA architecture and functions using domain-specific chromatin isolation by RNA purification. Nat Biotechnol 32:933-40|
|Schmitt, Adam M; Chang, Howard Y (2013) Gene regulation: Long RNAs wire up cancer growth. Nature 500:536-7|
|Batista, Pedro J; Chang, Howard Y (2013) Cytotopic localization by long noncoding RNAs. Curr Opin Cell Biol 25:195-9|
|Li, Lingjie; Liu, Bo; Wapinski, Orly L et al. (2013) Targeted disruption of Hotair leads to homeotic transformation and gene derepression. Cell Rep 5:3-12|
Showing the most recent 10 out of 30 publications