Edward P Gelmann

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• Branigan, G. L., Torrandell-Haro, G., Soto, M., Gelmann, E. P., Vitali, F., Rodgers, K. E., & Brinton, R. D. (2022). Androgen-targeting therapeutics mitigate the adverse effect of GnRH agonist on the risk of neurodegenerative disease in men treated for prostate cancer. Cancer medicine, 11(13), 2687-2698.
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  Prostate cancer and multiple neurodegenerative diseases (NDD) share an age-associated pattern of onset. Therapy of prostate cancer is known to impact cognitive function. The objective of this study was to determine the impact of multiple classes of androgen-targeting therapeutics (ATT) on the risk of NDD.
• Bowen, C., Shibata, M., Zhang, H., Bergren, S. K., Shen, M. M., & Gelmann, E. P. (2020). CRISPR/Cas9-Mediated Point Mutation in Prolongs Protein Half-Life and Reverses Effects Allelic Loss. Cancer research, 80(21), 4805-4814.
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  is the most commonly deleted gene in prostate cancer and is a gatekeeper suppressor. is haploinsufficient, and pathogenic reduction in protein levels may result from genetic loss, decreased transcription, and increased protein degradation caused by inflammation or PTEN loss. NKX3.1 acts by retarding proliferation, activating antioxidants, and enhancing DNA repair. DYRK1B-mediated phosphorylation at serine 185 of NKX3.1 leads to its polyubiquitination and proteasomal degradation. Because NKX3.1 protein levels are reduced, but never entirely lost, in prostate adenocarcinoma, enhancement of NKX3.1 protein levels represents a potential therapeutic strategy. As a proof of principle, we used CRISPR/Cas9-mediated editing to engineer a point mutation in murine to code for a serine to alanine missense at amino acid 186, the target for Dyrk1b phosphorylation. , and mice were analyzed over one year to determine the levels of Nkx3.1 expression and effects of the mutant protein on the prostate. Allelic loss of caused reduced levels of Nkx3.1 protein, increased proliferation, and prostate hyperplasia and dysplasia, whereas mouse prostates had increased levels of Nkx3.1 protein, reduced prostate size, normal histology, reduced proliferation, and increased DNA end labeling. At 2 months of age, when all mice had normal prostate histology, mice demonstrated indices of metabolic activation, DNA damage response, and stress response. These data suggest that modulation of Nkx3.1 levels alone can exert long-term control over premalignant changes and susceptibility to DNA damage in the prostate. SIGNIFICANCE: These findings show that prolonging the half-life of Nkx3.1 reduces proliferation, enhances DNA end-labeling, and protects from DNA damage, ultimately blocking the proneoplastic effects of allelic loss.
• Gelmann, E. P. (2020). CRISPR/Cas9-Mediated Point Mutation in Nkx3.1 Prolongs Protein Half-Life and Reverses Effects Nkx3.1 Allelic Loss. Cancer Research, 80, 4805-4814.
• Bowen, C., Ostrowski, M. C., Leone, G., & Gelmann, E. P. (2019). Loss of PTEN Accelerates NKX3.1 Degradation to Promote Prostate Cancer Progression. Cancer research, 79(16), 4124-4134.
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  is the most commonly deleted gene in prostate cancer and a gatekeeper suppressor. NKX3.1 is a growth suppressor, mediator of apoptosis, inducer of antioxidants, and enhancer of DNA repair. PTEN is a ubiquitous tumor suppressor that is often decreased in prostate cancer during tumor progression. Steady-state turnover of NKX3.1 is mediated by DYRK1B phosphorylation at NKX3.1 serine 185 that leads to polyubiquitination and proteasomal degradation. In this study, we show PTEN is an NKX3.1 phosphatase that protects NKX3.1 from degradation. PTEN specifically opposed phosphorylation at NKX3.1(S185) and prolonged NKX3.1 half-life. PTEN and NKX3.1 interacted primarily in the nucleus as loss of PTEN nuclear localization abrogated its ability to bind to and protect NKX3.1 from degradation. The effect of PTEN on NKX3.1 was mediated via rapid enzyme-substrate interaction. An effect of PTEN on gene transcription was seen , but not . In gene-targeted mice, Nkx3.1 expression significantly diminished shortly after loss of Pten expression in the prostate. Nkx3.1 loss primarily increased prostate epithelial cell proliferation . In these mice, mRNA was not affected by Pten expression. Thus, the prostate cancer suppressors PTEN and NKX3.1 interact and loss of PTEN is responsible, at least in part, for progressive loss of NKX3.1 that occurs during tumor progression. SIGNIFICANCE: PTEN functions as a phosphatase of NKX3.1, a gatekeeper suppressor of prostate cancer.
• Andrews, C., Fortier, B., Hayward, A., Lederman, R., Petersen, L., McBride, J., Petersen, D. C., Ajayi, O., Kachambwa, P., Seutloali, M., Shoko, A., Mokhosi, M., Hiller, R., Adams, M., Ongaco, C., Pugh, E., Romm, J., Shelford, T., Chinegwundoh, F., , Adusei, B., et al. (2018). Development, Evaluation, and Implementation of a Pan-African Cancer Research Network: Men of African Descent and Carcinoma of the Prostate. Journal of global oncology, 4, 1-14.
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  Cancer of the prostate (CaP) is the leading cancer among men in sub-Saharan Africa (SSA). A substantial proportion of these men with CaP are diagnosed at late (usually incurable) stages, yet little is known about the etiology of CaP in SSA.
• Leighton, X., Bera, A., Eidelman, O., Bubendorf, L., Zellweger, T., Banerjee, J., Gelmann, E. P., Pollard, H. B., & Srivastava, M. (2018). Tissue microarray analysis delineate potential prognostic role of Annexin A7 in prostate cancer progression. PloS one, 13(10), e0205837.
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  Annexin A7 (ANXA7) is a member of the multifunctional calcium or phospholipid-binding annexin gene family. While low levels of ANXA7 are associated with aggressive types of cancer, the clinical impact of ANXA7 in prostate cancer remains unclear. Tissue microarrays (TMA) have revealed several new molecular markers in human tumors. Herein, we have identified the prognostic impact of ANXA7 in a prostate cancer using a tissue microarray containing 637 different specimens.
• Neugut, A. I., & Gelmann, E. P. (2016). Treatment of the Prostate in the Presence of Metastases: Lessons from Other Solid Tumors. European urology, 69(5), 795-6.
• Zhang, H., Zheng, T., Chua, C. W., Shen, M., & Gelmann, E. P. (2016). Nkx3.1 controls the DNA repair response in the mouse prostate. The Prostate, 76(4), 402-8.
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  The human prostate tumor suppressor NKX3.1 mediates the DNA repair response and interacts with the androgen receptor to assure faithful completion of transcription thereby protecting against TMPRSS2-ERG gene fusion. To determine directly the effect of Nkx3.1 in vivo we studied the DNA repair response in prostates of mice with targeted deletion of Nkx3.1.
• Bowen, C., Zheng, T., & Gelmann, E. P. (2015). NKX3.1 Suppresses TMPRSS2-ERG Gene Rearrangement and Mediates Repair of Androgen Receptor-Induced DNA Damage. Cancer research, 75(13), 2686-98.
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  TMPRSS2 gene rearrangements occur at DNA breaks formed during androgen receptor-mediated transcription and activate expression of ETS transcription factors at the early stages of more than half of prostate cancers. NKX3.1, a prostate tumor suppressor that accelerates the DNA repair response, binds to androgen receptor at the ERG gene breakpoint and inhibits both the juxtaposition of the TMPRSS2 and ERG gene loci and also their recombination. NKX3.1 acts by accelerating DNA repair after androgen-induced transcriptional activation. NKX3.1 influences the recruitment of proteins that promote homology-directed DNA repair. Loss of NKX3.1 favors recruitment to the ERG gene breakpoint of proteins that promote error-prone nonhomologous end-joining. Analysis of prostate cancer tissues showed that the presence of a TMPRSS2-ERG rearrangement was highly correlated with lower levels of NKX3.1 expression consistent with the role of NKX3.1 as a suppressor of the pathogenic gene rearrangement.
• Song, L. N., Silva, J., Koller, A., Rosenthal, A., Chen, E. I., & Gelmann, E. P. (2015). The Tumor Suppressor NKX3.1 Is Targeted for Degradation by DYRK1B Kinase. Molecular cancer research : MCR, 13(5), 913-22.
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  NKX3.1 is a prostate-specific homeodomain protein and tumor suppressor whose expression is reduced in the earliest phases of prostatic neoplasia. NKX3.1 expression is not only diminished by genetic loss and methylation, but the protein itself is a target for accelerated degradation caused by inflammation that is common in the aging prostate gland. NKX3.1 degradation is activated by phosphorylation at C-terminal serine residues that mediate ubiquitination and protein turnover. Because NKX3.1 is haploinsufficient, strategies to increase its protein stability could lead to new therapies. Here, a high-throughput screen was developed using an siRNA library for kinases that mediate NKX3.1 degradation. This approach identified several candidates, of which DYRK1B, a kinase that is subject to gene amplification and overexpression in other cancers, had the greatest impact on NKX3.1 half-life. Mechanistically, NKX3.1 and DYRK1B were shown to interact via the DYRK1B kinase domain. In addition, an in vitro kinase assay showed that DYRK1B phosphorylated NKX3.1 at serine 185, a residue critical for NKX3.1 steady-state turnover. Lastly, small-molecule inhibitors of DYRK1B prolonged NKX3.1 half-life. Thus, DYRK1B is a target for enzymatic inhibition in order to increase cellular NKX3.1.
• Bowen, C., Ju, J. H., Lee, J. H., Paull, T. T., & Gelmann, E. P. (2013). Functional activation of ATM by the prostate cancer suppressor NKX3.1. Cell reports, 4(3), 516-29.
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  The prostate tumor suppressor NKX3.1 augments response to DNA damage and enhances survival after DNA damage. Within minutes of DNA damage, NKX3.1 undergoes phosphorylation at tyrosine 222, which is required for a functional interaction with ataxia telangiectasia mutated (ATM) kinase. NKX3.1 binds to the N-terminal region of ATM, accelerates ATM activation, and hastens the formation of γhistone2AX. NKX3.1 enhances DNA-dependent ATM kinase activation by both the MRN complex and H2O2 in a DNA-damage-independent manner. ATM, bound to the NKX3.1 homeodomain, phosphorylates NKX3.1, leading to ubiquitination and degradation. Thus, NKX3.1 and ATM have a functional interaction leading to ATM activation and then NKX3.1 degradation in a tightly regulated DNA damage response specific to prostate epithelial cells. These findings demonstrate a mechanism for the tumor-suppressor properties of NKX3.1, demonstrate how NKX3.1 may enhance DNA integrity in prostate stem cells and may help to explain how cells differ in their sensitivity to DNA damage.
• Lim, E., & Gelmann, E. P. (2013). Renal cell cancer treated with a single-edged sword. Cell reports, 3(2), 275-6.
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  Preclinical and early clinical data suggest that antiangiogenic treatments may lead to more aggressive tumors. In this issue of Cell Reports, Blagoev et al. (2013) show that sunitinib, a multikinase inhibitor with antiangiogenic effects, does not worsen the survival of patients with metastatic kidney cancer.
• Muhlbradt, E., Ma, J., Severi, G., Ortner, E., Hayes, V., Hoang, H. N., Stampfer, M., Giles, G., Pollak, M., & Gelmann, E. P. (2013). Variant NKX3.1 and Serum IGF-1: Investigation of Interaction in Prostate Cancer. Genes & cancer, 4(11-12), 535-45.
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  NKX3.1 is a tumor suppressor down-regulated in early prostate cancers. A SNP (rs2228013), which represents a polymorphic NKX3.1(C154T) coding for a variant protein NKX3.1(R52C), is present in 10% of the population and is related to prostatic enlargement and prostate cancer. We investigated rs2228013 in prostate cancer risk for 937 prostate cancer cases and 1,086 age-matched controls from a nested case-control study within the prospective Physicians' Health Study (PHS) and among 798 cases and 527 controls retrospectively collected in the Risk Factors for Prostate Cancer Study of the Victoria Cancer Council (RFPCS). We also investigated the interaction between serum IGF-I levels and NKX3.1 genotype in the populations from PHS and RFPCS. In the PHS, we found no overall association between the variant T allele in rs2228013 in NKX3.1 and prostate cancer risk (odd ratio = 1.25; 95% confidence interval = 0.92-1.71). A subgroup analysis for cases diagnosed before age 70 showed an increased risk (relative risk = 1.55; 95% confidence interval = 1.04-2.31) of overall prostate cancer. In this age-group, the risk of metastatic cancer at diagnosis or of fatal cancer was even higher in carriers of the T allele (relative risk = 2.15; 95% confidence interval = 1.00-4.63). These associations were not replicated in the RFPCS. Serum IGF-I levels were found to be a risk factor for prostate cancer in both study populations. The wild type NKX3.1 protein can induce IGFBP-3 expression in vitro. We report that variant NKX3.1 cannot induce IGFBP-3 expression, but the NKX3.1 genotype does not modify the association between serum IGF-I levels and prostate cancer risk.
• Song, L. N., Bowen, C., & Gelmann, E. P. (2013). Structural and functional interactions of the prostate cancer suppressor protein NKX3.1 with topoisomerase I. The Biochemical journal, 453(1), 125-36.
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  NKX3.1 (NK3 homeobox 1) is a prostate tumour suppressor protein with a number of activities that are critical for its role in tumour suppression. NKX3.1 mediates the cellular response to DNA damage by interacting with ATM (ataxia telangiectasia mutated) and by activation of topoisomerase I. In the present study we characterized the interaction between NKX3.1 and topoisomerase I. The NKX3.1 homeodomain binds to a region of topoisomerase I spanning the junction between the core and linker domains. Loss of the topoisomerase I N-terminal domain, a region for frequent protein interactions, did not affect binding to NKX3.1 as was shown by the activation of Topo70 (N-terminal truncated topoisomerase I) in vitro. In contrast, NKX3.1 interacts with the enzyme reconstituted from peptide fragments of the core and linker active site domains, but inhibits the DNA-resolving activity of the reconstituted enzyme in vitro. The effect of NKX3.1 on both Topo70 and the reconstituted enzyme was seen in the presence and absence of camptothecin. Neither NKX3.1 nor CPT (camptothecin) had an effect on the interaction of the other with topoisomerase I. Therefore the interactions of NKX3.1 and CPT with the linker domain of topoisomerase I are mutually exclusive. However, in cells the effect of NKX3.1 on topoisomerase binding to DNA sensitized the cells to cellular toxicity and the induction of apoptosis by low doses of CPT. Lastly, topoisomerase I is important for the effect of NKX3.1 on cell survival after DNA damage as topoisomerase knockdown blocked the effect of NKX3.1 on clonogenicity after DNA damage. Therefore NKX3.1 and topoisomerase I interact in vitro and in cells to affect the CPT sensitivity and DNA-repair functions of NKX3.1.
• Ruiz, C., Oeggerli, M., Germann, M., Gluderer, S., Stocker, H., Andreozzi, M., Thalmann, G. N., Cecchini, M. G., Zellweger, T., Stürm, S., Koivisto, P. A., Helin, H. J., Gelmann, E. P., Glass, A. G., Gasser, T. C., Terracciano, L. M., Bachmann, A., Wyler, S., Bubendorf, L., & Rentsch, C. A. (2012). High NRBP1 expression in prostate cancer is linked with poor clinical outcomes and increased cancer cell growth. The Prostate, 72(15), 1678-87.
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  We recently established the rationale that NRBP1 (nuclear receptor binding protein 1) has a potential growth-promoting role in cell biology. NRBP1 interacts directly with TSC-22, a potential tumor suppressor gene that is differently expressed in prostate cancer. Consequently, we analyzed the role of NRBP1 expression in prostate cancer cell lines and its expression on prostate cancer tissue microarrays (TMA).
• Beildeck, M. E., Gelmann, E. P., & Byers, S. W. (2010). Cross-regulation of signaling pathways: an example of nuclear hormone receptors and the canonical Wnt pathway. Experimental cell research, 316(11), 1763-72.
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  Predicting the potential physiological outcome(s) of any given molecular pathway is complex because of cross-talk with other pathways. This is particularly evident in the case of the nuclear hormone receptor and canonical Wnt pathways, which regulate cell growth and proliferation, differentiation, apoptosis, and metastatic potential in numerous tissues. These pathways are known to intersect at many levels: in the intracellular space, at the membrane, in the cytoplasm, and within the nucleus. The outcomes of these interactions are important in the control of stem cell differentiation and maintenance, feedback loops, and regulating oncogenic potential. The aim of this review is to demonstrate the importance of considering pathway cross-talk when predicting functional outcomes of signaling, using nuclear hormone receptor/canonical Wnt pathway cross-talk as an example.
• Bowen, C., & Gelmann, E. P. (2010). NKX3.1 activates cellular response to DNA damage. Cancer research, 70(8), 3089-97.
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  The prostate-specific tumor suppressor homeodomain protein NKX3.1 is inactivated by a variety of mechanisms in the earliest phases of prostate carcinogenesis and in premalignant regions of the prostate gland. The mechanisms by which NKX3.1 exercises tumor suppression have not been well elucidated. Here, we show that NKX3.1 affects DNA damage response and cell survival after DNA damage. NKX3.1 expression in PC-3 prostate cancer cells enhances colony formation after DNA damage but has minimal effect on apoptosis. NKX3.1 also diminishes and regulates total cellular accumulation of gammaH2AX. Endogenous NKX3.1 in LNCaP cells localizes to sites of DNA damage where it affects the recruitment of phosphorylated ATM and the phosphorylation of H2AX. Knockdown of NKX3.1 in LNCaP cells attenuates the acute responses of both ATM and H2AX phosphorylation to DNA damage and their subnuclear localization to DNA damage sites. NKX3.1 expression enhances activation of ATM as assayed by autophosphorylation at serine 1981 and activation of ATR as assayed by phosphorylation of CHK1. An inherited mutation of NKX3.1 that predisposes to early prostate cancer and attenuates in vitro DNA binding was devoid of the ability to activate ATM and to colocalize with gammaH2AX at foci of DNA damage. These data show a novel mechanism by which a homeoprotein can affect DNA damage repair and act as a tumor suppressor.