• Welcome to the Hollenhorst Lab at IU

  • Research

    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

    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

    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

    Ben Greulich

    Cell, Molecular and Cancer Biology Graduate Student

    B.S. Biochemistry Indiana University

    Renee Kinne

    Cell, Molecular and Cancer Biology Graduate Student

    B.S. Michigan State University

     

    Yiling Dong

    Undergraduate Researcher

     

    Gracie Baker

    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

     

  • 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 Research
     
    Tomar, 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 414:190-204
     
    Adelaiye-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): 6651-6666
     
    Kedage, 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): 17225-17235
     
    Plotnik, 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):4452-4462
     
    Kedage, 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.
     
     

     

  • News

    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

    October 2018

    Taylor Nicholas presented her research at the ASBMB Transcription meeting in Snowbird UT

    June 2018

    Justin Budka published his paper on the role of ELF1 in prostate cancer and successfully defended his thesis, congrats Dr. Budka!

    April 2018

    Ben Greulich was awarded an Indiana CTSI predoctoral fellowship to support his work. Congrats Ben!

    Jan 2018

    Brady Strittmatter received the Peglow Award for outstanding performance in the Biochemistry Preliminary Examination. Congrats Brady!

  • 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