MICaB Graduate Program
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Scott M. Dehm, Ph.D.
Department of Laboratory Medicine & Pathology
University of Saskatchewan, 2003, Ph.D.
Androgen receptor activation in prostate cancer
Research in the Dehm laboratory focuses on the role of the androgen receptor in prostate cancer development and progression. The androgen receptor is a nuclear steroid receptor transcription factor that responds to the physiologic androgens testosterone and dihydrotestosterone. Traditionally, treatment for metastatic prostate cancer has depended on blocking the production or action of these androgens in order to inhibit the growth and survival promoting functions of the androgen receptor. Androgen depletion is therefore one of the earliest examples of targeted cancer therapy. The primary limitation of androgen depletion is that prostate cancer will eventually develop resistance and recur with a lethal castration-resistant phenotype. Our laboratory studies the changes that occur in the therapeutic target (the androgen receptor) in response to the targeted therapy (androgen depletion) to understand the mechanisms underlying this progression to therapy-resistant disease. Our approach is to employ a variety of genomic, molecular biology, and biochemistry tools to study prostate cancer progression in clinical prostate cancer specimens as well as cell- and xenograft-based models of the disease. Our ultimate goal is to develop new AR-targeted therapies that could more effectively and durably suppress prostate cancer growth.
Selected Recent Publications:
- Nyquist MD, Li, Y, Hwang TH, Manlove LS, Vessella RL, Silverstein KAT, Voytas DF, Dehm SM. 2013. TALEN-Engineered AR Gene Rearrangements Reveal Endocrine Uncoupling of Androgen Receptor in Prostate Cancer. Proc. Natl. Acad. Sci. USA, 110:17492-7.
- Dehm SM. 2013. Test-firing ammunition for spliceosome inhibition in cancer. Cancer Research, In Press.
- Dehm SM. 2013. Alternatively spliced protein variants: exploiting modularity to outwit cancer therapy. Cancer Research, 73:5309-14.
- Bohrer, LR, Liu P, Zhong J, Pan Y, Angstman J, Brand LJ, Dehm SM*, Huang H*. 2013. FOXO1 binds to the TAU5 motif and inhibits constitutively active androgen receptor splice variants. The Prostate, 73:1017-27. *Corresponding authors
- Nyquist MD, Dehm SM. 2013. Interplay between genomic alterations and androgen receptor signaling during prostate cancer development and progression. Hormones and Cancer, 4:61-9.
- Brand LJ, Dehm SM. 2013. Androgen receptor gene rearrangements: new perspectives on prostate cancer progression. Current Drug Targets, 14:441-9.
- Li Y, Chan SC, Brand LJ, Hwang TH, Silverstein KA, Dehm SM. 2013. Androgen receptor splice variants mediate enzalutamide resistance in castration-resistant prostate cancer cell lines. Cancer Res., 73:483-9.
- Kohli M, Qin R, Jimenez R, Dehm SM. 2012. Biomarker-based targeting of the androgen-androgen receptor axis in advanced prostate cancer. Adv. Urol., 2012:781459.
- Chan SC, Li Y, Dehm SM. 2012. Androgen receptor splice variants activate AR target genes and support aberrant prostate cancer cell growth independent of the canonical AR nuclear localization signal. J. Biol. Chem., 287:19736-49.
- Li Y, Hwang TH, Oseth LA, Hauge A, Vessella RL, Schmechel SC, Hirsch B, Beckman KB, Silverstein KA, Dehm SM. 2012. AR intragenic deletions linked to androgen receptor splice variant expression and activity in models of prostate cancer progression. Oncogene, 31:4759-67.
- Dehm SM, Tindall DJ. 2011. Alternatively spliced androgen receptor variants. Endocr Relat Cancer. Sep 20;18(5):R183-96.
- Li Y, Alsagabi M, Fan D, Bova GS, Tewfik AH, Dehm SM. 2011. Intragenic rearrangement and altered RNA splicing of the androgen receptor in a cell-based model of prostate cancer progression. Cancer Res. Mar 15;71(6):2108-17.
- Shin S, Kim TD, Jin F, van Deursen JM, Dehm SM, Tindall DJ, Grande JP, Munz JM, Vasmatzis G, Janknecht R. 2009. Induction of prostatic intraepithelial neoplasia and modulation of androgen receptor by ETS variant 1/ETS-related protein 81. Cancer Res., 69: 8102-10.
- Raclaw KA, Heemers HV, Kidd EM, Dehm SM, Tindall DJ. 2008. Induction of FLIP expression by androgens protects prostate cancer cells from TRAIL-mediated apoptosis. The Prostate, 68: 1696-706.
- Dehm SM, Schmidt LJ, Heemers HV, Vessella RL, Tindall DJ. 2008. Splicing of a novel AR exon generates a constitutively active androgen receptor that mediates prostate cancer therapy resistance. Cancer Res., 68: 5469-77.
- Heemers HV, Regan KM, Dehm SM, Tindall DJ. 2007. Androgen induction of the androgen receptor co-activator FHL2: evidence for a role for serum response factor in prostate cancer. Cancer Res., 67 :10592-9.
- Dehm SM, Regan KM, Schmidt, LJ, Tindall DJ. 2007. Selective role of an NH2-terminal WxxLF motif for aberrant androgen receptor activation in androgen depletion-independent prostate cancer cells. Cancer Res. 67: 10067-77.
- Dehm SM, Tindall DJ. 2007. Androgen Receptor Structural and Functional Elements: Role and Regulation in Prostate Cancer. Mol. Endocrinology. 2: 2855-63.
- Dehm SM, Tindall DJ. 2006. Ligand-independent androgen receptor activity is activation function-2-independent and resistant to antiandrogens in androgen refractory prostate cancer cells.J. Biol. Chem. 28:27882-93.
- Dehm SM, Tindall DJ. 2006. Molecular regulation of androgen action in prostate cancer. J. Cell Biochem. 99:333-44.
- Debes JD, Comuzzi B, Schmidt LJ, Dehm SM, Culig Z, Tindall DJ. 2005. p300 regulates androgen receptor-independent expression of prostate-specific antigen in prostate cancer cells treated chronically with interleukin-6. Cancer Res. 65, 5965-73.
- Dehm SM, Tindall DJ. 2005. Regulation of androgen receptor signaling in prostate cancer. Expert Rev. Anticancer Ther. 5: 63-74.