Welcome to the Hollenhorst Lab at IU
About the Lab
Our research focuses on an important basic science question and an important cancer biology question.
Basic Science: How do transcription factors with similar DNA binding domains achieve specificity?
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 if they have different biological functions 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.
Some examples of our work include the very first use of the genomic approaches of ChIP-chip (Hollenhorst et al. 2007 Genes and Development) and ChIP-seq (Hollenhorst et al. 2009 PLoS Genetics) to compare DNA binding specificity in vivo in a mammalian transcription factor family. 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.
Cancer Biology: What are the molecular mechanisms that allow transcription factors expressed due to gene fusions to promoter 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. We are in the process of working with collaborators to turn some of these discoveries into therapies that can be translated to the clinic. We have also been discovering interesting similarities between the molecular mechanisms in all three diseases. For example, the EWS protein that interacts with oncogenic transcription factors (as diagrammed above) is the same protein whose N-terminus is fused to FLI1 in the Ewing sarcoma gene rearrangement. If we disrupt the interaction between ERG and EWS using a point mutant of ERG that cannot bind EWS (ERG P436A) we can eliminate the ability of ERG to promote prostate cancer in a mouse model (Kedage et al. 2016 Cell Reports).
Join our group
We sometimes have postdoctoral opportunities available. Contact Dr. Hollenhorst for details.
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
B.S., Indiana University
Dr. Stephanie Metcalf
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
Cell, Molecular and Cancer Biology Graduate Student
M.S. Biochemistry, Indiana University School of Medicine
B.A. Cellular and Molecular Biology DePauw University
Cell, Molecular and Cancer Biology Graduate Student
B.S. Biochemistry Indiana University
Cell, Molecular and Cancer Biology Graduate Student
B.S. Michigan State University
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
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.Selvaraj, N., Kedage, V., and P.C. Hollenhorst. (2015). Comparison of MAPK specificity across the ETS transcription factor family identifies a high-affinity ERK interaction required for ERG function in prostate cells.Cell Communication and Signaling 13:12.Selvaraj, N., Budka, J.A., Ferris, M.W., Plotnik, J.P., and P.C. Hollenhorst. (2015). Extracellular signal-regulated kinase signaling regulates the opposing roles of JUN family transcription factors at ETS/AP-1 sites and in cell migration. Molecular and Cellular Biology 35(1): 88-100.Plotnik, J.P., Budka, J.A., Ferris, M.W., and P.C. Hollenhorst. (2014). ETS1 is a genome-wide effector of RAS/ERK signaling in epithelial cells. Nucleic Acids Research 42(19): 11928-40.Selvaraj, N., Budka, J.A., Ferris, M.W., Jerde, T.J., and P.C. Hollenhorst. (2014). Prostate cancer ETS rearrangements switch a cell migration gene expression program from RAS/ERK to PI3K/AKT regulation.Molecular Cancer 13:61.
Brady Strittmatter published his thesis research in PLoS Genetics and defended his thesis. Congrats Dr. Strittmatter!
Taylor Nicholas published her paper identifying an inhibitor of the ERG/EWS interaction in PLoS One and successfully defended her thesis. Congrats Dr. Nicholas!
Ben Greulich received the Medical Sciences Program Doane and Eunice Wright fellowship to support his work in the lab. Congrats Ben!
Brady Strittmatter presented his research at the AACR Annual Meeting in Atlanta GA
Taylor Nicholas presented her research at the ASBMB Transcription meeting in Snowbird UT
Justin Budka published his paper on the role of ELF1 in prostate cancer and successfully defended his thesis, congrats Dr. Budka!
Ben Greulich was awarded an Indiana CTSI predoctoral fellowship to support his work. Congrats Ben!
Brady Strittmatter received the Peglow Award for outstanding performance in the Biochemistry Preliminary Examination. Congrats Brady!
We are located in Jordan Hall,
Peter's email is pchollen@
Peter's office phone: 812-855-1151
Hollenhorst lab phone: 812-856-7608
Research in the Hollenhorst Lab is supported by...
Genitourinary Malignancies Pilot Funding
Funding for Brady Strittmatter
Funding for Ben Greulich
National Cancer Institute R01