Welcome to the Hollenhorst Lab at IU
Research
About the Lab
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).
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?
Join our group
Graduate Students
We accept graduate students through the following programs:
Postdoctoral Fellows
We sometimes have postdoctoral opportunities available. Contact Dr. Hollenhorst for details.
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
Former Lab Members
Nagarithinam Selvaraj (former postdoc) - Developmental Scientist II, Leidos Biomedical Research, Frederick MD
Justin Budka (former graduate student) - Research Scientist, Kite Pharma, Santa Monica CA
Josh Plotnik (former graduate student) - Senior Scientist, AbbVie, North Chicago IL
Vivek Kedage (former graduate student) - Scientist, MedGenome, Foster City CA
Taylor Nicholas (former graduate student) - Postdoctoral Fellow, Fred Hutchinson Cancer Research Center
Brady Strittmatter (former graduate student) - Postdoctoral Fellow, Northwestern University Feinberg School of Medicine
Ben Greulich (former graduate student) - Postdoctoral Fellow, Duke University School of Medicine
Publications
Nicholas, T.R., Metcalf, S.A., Greulich, B.M., and P.C. Hollenhorst. (2021) Androgen signaling connects short isoform production to breakpoint formation at Ewing sarcoma breakpoint region 1. NAR Cancer 3(3), zcab033.Strittmatter, B.G., Jerde, T.J., and P.C. Hollenhorst. (2021) Ras/ERK and PI3K/AKT signaling differentially regulate oncogenic ERG mediated transcription in prostate cells. PLoS Genetics 17(7):e1009708.Greulich, B.M., Plotnik, J.P., Jerde, T.J., and P.C. Hollenhorst. (2021) Toll-like receptor 4 signaling activates ERG function in prostate cancer and provides a therapeutic target. NAR Cancer 3(1), zcaa046.Nicholas, T.R., Meng, J., Greulich, B.M., Morris, T.S., and P.C. Hollenhorst. (2020) A high-throughput screen identifies inhibitors of the interaction between the oncogenic transcription factor ERG and the cofactor EWS. PLoS One 15(9):e0238999.Budka, J.A., Ferris, M.W., Capone, M.J., and P.C. Hollenhorst. (2018) Common ELF1 deletion in prostate cancer bolsters oncogenic ETS function, inhibits senescence and promotes docetaxel resistance. Genes and Cancer 9:198-214.Damayanti, N.P., Budka, J.A., Khella, H.W.Z., Ferris, M.W., Ku, S.Y., Kauffman, E., Wood, A.C., Ahmed, K., Chintala, V.N., Adelaiye-Ogala, R., Elbanna, M., Orillion, A., Chintala, S., Kao, C., Linehan, W.M., Yousef, G.M., Hollenhorst, P.C., and R. Pili. (2018). Therapeutic targeting of TFE3/IRS-1/PI3K/mTOR axis in translocation renal cell carcinoma. Clinical Cancer ResearchTomar, S., Plotnik, J.P., Haley, J., Scantland, J., Dasari, S., Sheikh, Z., Emerson, R., Lenz, D., Hollenhorst, P.C., and A.K. Mitra. (2017). ETS1 induction by the microenvironment promotes ovarian cancer metastasis through focal adhesion kinase. Cancer Letters 414:190-204Adelaiye-Ogala, R., Budka, J., Damayanti, N.P., Arrington, J., Ferris, M.W., Hsu, C.C., Chintala, S., Orillion, A.R., Miles, K.M., Shen, L., Elbanna, M., Ciamporcero, E., Arisa, S., Pettazzoni, P., Draetta, G.F., Seshadri, M., Hancock, B.A., Radovich, M., Kota, J., Buck, M., Keilhack, H., McCarthy, B.P., Persohn, S.A., Territo, P.R., Zang, Y., Irudayaraj, J., Tao, A.W., Hollenhorst, P., and R. Pili. (2017). EZH2 modifies sunitinib resistance in renal cell carcinoma by kinome reprogramming. Cancer Research 77(23): 6651-6666Kedage, V., Strittmatter, B.G., Dausinas, P.B., and P.C. Hollenhorst. (2017). Phosphorylation of the oncogenic transcription factor ERG in prostate cells dissociates polycomb repressive complex 2 allowing target gene activation. Journal of Biological Chemistry 292(42): 17225-17235Plotnik, J.P. and P.C. Hollenhorst. (2017). Genome-wide analysis of RAS/ERK signaling targets. Methods in Molecular Biology 1487:277-288.Plotnik, J.P. and P.C. Hollenhorst. (2017). Interaction with ZMYND11 mediates opposing roles of Ras-responsive transcription factors ETS1 and ETS2. Nucleic Acids Research 45(8):4452-4462Kedage, V., Selvaraj, N., Nicholas, T.R., Budka, J.A., Plotnik, J.P., Jerde, T.J., and P.C. Hollenhorst. (2016). An interaction with Ewing's sarcoma breakpoint protein EWS defines a specific oncogenic mechanism of ETS factors rearranged in prostate cancer. Cell Reports 17(5): 1289-1301.
News
Feb 2022
Stephanie Metcalf was awarded an American Cancer Society Postdoctoral Fellowship. Congrats Dr. Metcalf!
May 2021
Brady Strittmatter published his thesis research in PLoS Genetics and defended his thesis. Congrats Dr. Strittmatter!
May 2020
Taylor Nicholas published her paper identifying an inhibitor of the ERG/EWS interaction in PLoS One and successfully defended her thesis. Congrats Dr. Nicholas!
Feb 2020
Ben Greulich received the Medical Sciences Program Doane and Eunice Wright fellowship to support his work in the lab. Congrats Ben!
April 2019
Brady Strittmatter presented his research at the AACR Annual Meeting in Atlanta GA
Contact Us
We are located in Jordan Hall,
Indiana University
Bloomington, Indiana
Peter's email is pchollen@
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
© 2017