Chonghui Cheng

Chonghui Cheng, MD, PhD
Assistant Professor
Medicine


RNA regulation of EMT and breast cancer

Research cluster: Cancer Biology

E-mail:   
chengc@northwestern.edu

Current research in the Cheng lab focuses on investigating how RNA regulation controls epithelial-mesenchymal transition (EMT) and breast cancer progression. EMT plays a fundamental role in normal developmental processes including mesoderm and neural tube formation. However, when abnormally activated, EMT promotes tumor metastasis and recurrence. Thus, understanding the mechanisms by which EMT is regulated is critical to advance the diagnosis, prognosis, and treatment of cancer.

It is now known that alternative RNA splicing occurs in nearly all human genes. Alternative splicing allows for production of multiple protein isoforms from a single gene and serves as a key mechanism for generating protein diversity.  While aberrant alternative splicing has been observed in cancer for over a decade, whether alternative splicing plays a functional role in cancer has remained largely unexplored.

Recent work from our lab revealed a novel mechanism by which alternative RNA splicing causally controls EMT and breast cancer progression. Using the cancer stem cell marker CD44 as a model, we found that CD44 alternative splicing is tightly regulated by splicing factors during EMT, resulting in a switch in isoform expression from CD44v in epithelial cells to CD44s in mesenchymal cells. Interestingly, this switch in expression to the CD44s isoform is required for cells to undergo EMT and is essential for recurrent tumor formation in mice. Furthermore, analysis of patient breast tumor specimens indicates that CD44s expression correlates with a more aggressive breast tumor phenotype in patients. These data suggest that regulation at the level of alternative splicing constitutes a critical mechanism in controlling EMT and cancer progression.

We are currently investigating the role of alternative RNA splicing in breast cancer by addressing two fundamental questions: 1) What is the role of alternatively spliced isoforms in EMT and breast cancer progression? 2) How do signaling and splicing factors regulate alternative splicing that, in turn, cause a cancerous phenotype? We hope that our research will provide a mechanistic paradigm on how regulated alternative splicing controls cancer pathogenesis.

Selected Publications:

 

Zhao P, Damerow M, Stern P, Liu A, Sweet-Cordero A, Siziopikou K, Neilson JR, Sharp PA, and Cheng C. (2012) CD44 promotes Kras-dependent lung adenocarcinoma. Oncogene [In Press]

Reinke LM, Xu Y, Cheng C (2012) Snail Represses the Splicing Regulator ESRP1 to Promote Epithelial-Mesenchymal Transition. J Biol Chem. 287:36435-42.

Brown RL, Reinke LM, Damerow MS, Perez D, Chodosh LA, Yang J, Cheng C (2011)  CD44 splice isoform switching in human and mouse epithelium is essential for epithelial-mesenchymal transition and breast cancer progression. J Clin Invest. 121:1064-74. Highlighted in Nat Med., Commented in Breast Cancer Res., Recommended by Faculty 1000.

Cheng C, Yaffe MB, Sharp PA (2006) A positive feedback loop couples Ras activation and CD44 alternative splicing. Genes Dev.  20: 1715-1720.

Cheng C, Sharp PA (2006) SRm160 mediates CD44 alternative splicing and influences tumor cell invasion. Mol Cell Biol  26: 362-370.

Cheng C, Sharp PA (2003) RNA polymerase II accumulation in the promoter-proximal region of the dihydrofolate reductase and gamma-actin genes. Mol Cell Biol  23: 1961-1967.


Pub med

View Publications by Chonghui Cheng listed in the National Library of Medicine (PubMed).