Welcome to the Hollenhorst Lab at IU
Research
About the Lab
Specificity of oncogenic transcription factors
Transcription factors are proteins that bind to specific places in the genome and regulate which genes should be turned on or off. Humans have almost 2000 transcription factors that can be grouped into "families" of factors with similar DNA binding domains. Due to the similarity of these DNA binding domains, most members of transcription factor families are thought to bind to similar DNA sequences. Despite this similarity, different members of transcription factor families can have very different biological functions. How does this work? If these factors bind the same sequence you would expect them to bind to the same gene targets. But we know that similar transcription factors can have very different biological functions, and in that case you would expect them to activate or repress different genes. One example of this conundrum is the ETS family of transcription factors. There are 28 ETS transcription factors in the human genome. They all bind to a very similar DNA sequence in vitro. However, they all have very different biological functions in vivo. For example, some ETS proteins cause cancer (oncogenes), some inhibit cancer formation (tumor suppressors), and some have no role in cancer. We are leaders in the use of both genomic and biochemical techniques to uncover molecular mechanisms that differentiate function in the ETS and other transcription factor families.
One of our more recent studies (Kedage et al. 2016 Cell Reports) used biochemistry to show that the four ETS transcription factors that can cause prostate cancer are the only four ETS family members that bind to the co-activator EWS. This identified a molecular mechanism of oncogenic specificity in the ETS family. Because the EWS/ETS interaction is so specific for oncogenic transcription factors, it represents an ideal drug target. We have recently performed a small-molecule screen to identify compounds that can inhibit this protein-protein interaction (Nicholas et al. 2020 PLoS One).
What are the molecular mechanisms that allow transcription factors expressed due to gene fusions to promote cancer?
The TMPRSS2:ERG gene fusion is the most common genomic alteration in prostate cancer. It results in expression of the transcription factor ERG in adult prostate cells, a cell type where ERG is normally silent.
The EWS:FLI1 gene fusion is the causative lesion in 95% of Ewing sarcoma cases. It results in expression of a chimeric protein that includes the N-terminus of EWS and C-terminus of the transcription factor FLI1.
Various fusions with the transcription factor TFE3 cause a rare but deadly form of renal cell carcinoma (tRCC).
We study all three of these diseases in an attempt to identify key molecular mechanisms that can be targeted for therapeutic development. Interestingly, if we artificially fuse the N-terminus of EWS to any ETS family transcription factor, it allow that fusion protein to function like ERG and drive cell migration in prostate epithelial cells (Kedage et al 2016 Cell Reports). What is the key to this function? The N-terminus of EWS is intrinsically disordered and can drive phase separation. Does this play a role?
How does signaling regulate ERG function in prostate cancer?
Both the Ras/MAPK and PI3K/AKT pathway are important for ERG to promote prostate cancer. We have shown that MAPK signaling allows ERK to phosphorylate ERG, resulting in the loss of an interaction between ERG and the co-repressor EZH2 (Kedage et al. 2017 JBC). ERK is recruited to phosphorylate ERG only at certain regions of the genome. This way, ERK recruitment acts like a switch to control which genes ERG activates, and which genes ERG represses (Strittmatter et al. 2021 PLoS Genetics). We have also shown that the PI3K/AKT pathway can alter the ERG cistrome, allowing ERG to bind to genes that regulate the differentiation of prostate cells to a luminal epithelial cell state (Strittmatter et al. 2021 PLoS Genetics). We are currently using single-cell RNA sequencing experiments to determine how the interplay between Ras/MAPK and PI3K/AKT signaling regulate ERG function across distinct cell types within prostate tumors.Lab Members
Dr. Peter C. Hollenhorst
Associate Professor of Biochemistry & Molecular Biology, Medical Sciences Program
B.S. Chemistry and Biology, St. Norbert College
Ph.D. Biomolecular Chemistry, University of Wisconsin-Madison
American Cancer Society Postdoctoral Fellow, Huntsman Cancer Institute, University of Utah
Stevie Morris
Lab Manager
B.S., Indiana University
Dr. Stephanie Metcalf
American Cancer Society Postdoctoral Fellow
Ph.D. Louisville
B.S. IUPUI
Dr. Saranya Rajendran
Assistant Research Professor
Postdoctoral Associate, Yale University
Ph.D. Biotechnology, Anna University
M.S. University of Madras
B.S. Lady Doak College
Nick Downing
Cell, Molecular and Cancer Biology Graduate Student
M.S. Biochemistry, Indiana University School of Medicine
B.A. Cellular and Molecular Biology DePauw University
Michael Kwakye
Biotechnology Masters Student
B.S. Biology Indiana University
Renee Kinne
Cell, Molecular and Cancer Biology Graduate Student
B.S. Michigan State University
Lauren Konig
Undergraduate Researcher
Alex Kritzer
Undergraduate Researcher
Kiah Royse
Undergraduate Researcher
Contact Us
We are located in Jordan Hall,
Indiana University
Bloomington, Indiana
Peter's email is pchollen@
indiana.edu 
Peter's office phone: 812-855-1151
Hollenhorst lab phone: 812-856-7608
Funding
Research in the Hollenhorst Lab is supported by...
Genitourinary Malignancies Pilot Funding
Funding for Brady Strittmatter
Funding for Ben Greulich
National Cancer Institute R01
