The University of Texas Health Science Center at Houston
McGovern Medical School
Department of Neurosurgery
Our research focuses on understanding the role of microRNAs and their post-transcriptional regulators in developmental and cancer biology. We and others have shown that microRNA expression is dysregulated in cancer and demonstrated using mouse models a direct role for these non-coding RNAs in cancer initiation, progression, and metastasis. We are particularly interested in the tumor suppressor let-7 microRNA family and the mechanisms regulating its expression.
Recent and provocative evidence suggests a novel form of post-transcriptional gene regulation involving 3' RNA uridylation mediated by Terminal Uridylyl Transferases (TUTases) as a critical driver of tumorigenesis. These data indicate that dysregulated TUTase activity alone and in concert with the onco-fetal LIN28/let-7 pathway are hallmarks of poor prognosis in multiple cancer types. Recently, we demonstrated that LIN28A recruits the TUTase ZCCHC11 to pre-let-7, where the addition of a short polyU-tail blocks microRNA processing and tumor suppressor function. We hypothesize that TUTases are viable molecular targets for cancer therapies as these enzymes are co-opted by malignancies to inactivate tumor suppressors via 3'RNA uridylation.
Our research addresses several fundamentally important questions:
- What is the widespread significance of 3' RNA uridylation in post-transcriptional gene regulation?
- How do TUTases and LIN28 contribute molecularly to cancer development and progression?
- Are TUTase and/or LIN28 inhibitors identifiable and potential cancer therapeutics?
- What developmental functions are performed by specific TUTases and LIN28A/B?
In a research rotation, the functional significance of 3' RNA uridylation by the TUTases will be interrogated in cancer cells using loss-of-function approaches (RNAi and CrispR/Cas9 systems) with an emphasis on perturbed cellular properties (proliferation, apoptosis, migration, etc...) and their underlying causative defects in microRNA biogenesis and mRNA turnover. Ongoing research in the lab is also seeking to identify small molecules that hold promise for treating ~15% of all cancers that are characterized by LIN28 expression and poor prognosis.
Students rotating in the Hagan laboratory would learn:
- A range of molecular biology techniques as well as bioinformatic methods
- These skills include DNA subcloning, RT-qPCR, Westerns, expression and purification of tagged mammalian proteins, mammalian tissue culture including mouse ES and human cancer cells, mining of publicly available datasets, and mouse work
Education & Training
PhD, University of Pittsburgh, 1998