Prostate Cell News Volume 10.24 | Jul 5 2019

TOP STORY

FOXA1 Mutations Alter Pioneering Activity, Differentiation and Prostate Cancer Phenotypes

Interrogation of the biological properties of wild-type FOXA1 and fourteen FOXA1 mutants revealed gain of function in mouse prostate organoid proliferation assays. Twelve of these mutants, as well as wild-type FOXA1, promoted an exaggerated pro-luminal differentiation program, whereas two different R219 mutants blocked luminal differentiation and activated a mesenchymal and neuroendocrine transcriptional program. [Nature] Abstract

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Selective Targeting of PARP-2 Inhibits Androgen Receptor Signaling and Prostate Cancer Growth through Disruption of FOXA1 Function

Selective targeting of poly(ADP-ribose) polymerase (PARP)-2 by genetic or pharmacological means blocked interaction between PARP-2 and FOXA1, which in turn attenuated androgen receptor (AR)-mediated gene expression and inhibited AR-positive prostate cancer growth. [Proc Natl Acad Sci USA] Abstract

Pleiotropic Impact of DNA-PK in Cancer and Implications for Therapeutic Strategies

DNA-dependent protein kinase catalytic subunit (DNA-PK) function was modulated using both genetic and pharmacologic methods in a series of in vitro models, in vivo xenografts, and patient-derived explants, and the impact on the downstream signaling and cellular cancer phenotypes was discerned. [Clin Cancer Res] Abstract | Editorial

DNA-Dependent Protein Kinase Drives Prostate Cancer Progression through Transcriptional Regulation of the Wnt Signaling Pathway

DNA-dependent protein kinase (DNAPK) was identified as the most significant kinase associated with metastatic progression in high-risk prostate cancer. Inhibition of DNAPK suppressed the growth of both AR-dependent and AR-independent prostate cancer cells. Gene set enrichment analysis nominated Wnt as the top pathway associated with DNAPK. [Clin Cancer Res] Abstract

Discovery of a Novel Long Noncoding RNA Overlapping the LCK Gene That Regulates Prostate Cancer Cell Growth

There was a significant positive correlation between hormone-upregulated long noncoding RNA within lymphocyte-specific protein tyrosine kinase (LCK) (HULLK) expression and high-grade prostate cancer (PCa) in multiple cohorts. shRNAs targeting HULLK significantly decreased PCa cell growth. Moreover, cells overexpressing HULLK were hypersensitive to androgen stimulation. [Mol Cancer] Full Article

TRAF6 Function as a Novel Co-Regulator of Wnt3a Target Genes in Prostate Cancer

Wnt3a-treatment promoted binding of tumor necrosis factor receptor associated factor 6 (TRAF6) to the Wnt co-receptors LRP5/LRP6 in PC3U and LNCaP cells in vitro. TRAF6 positively regulated mRNA expression of β-catenin and subsequent activation of Wnt target genes in PC3U cells. Wnt3a-induced invasion of PC3U and SW480 cells were significantly reduced when TRAF6 was silenced by siRNA. [EBioMedicine] Full Article

IFITM3 Promotes Bone Metastasis of Prostate Cancer Cells by Mediating Activation of the TGF-β Signaling Pathway

Scientists found that interferon-inducible transmembrane protein 3 (IFITM3) played a key role in the regulation of malignant tumor cell proliferation, invasion, and bone migration by binding to Smad4, thus activating the transforming growth factor β (TGF-β)-Smads signaling pathway. They showed that IFITM3 knockdown could alter the MAPK pathway associated with TGF-β-Smads signaling. [Cell Death Dis] Full Article

STAT5a/B Deficiency Delays, but Does Not Prevent, Prolactin-Driven Prostate Tumorigenesis in Mice

Stat5a/b deletion reversed the accumulation of stem/progenitor cells, indicating that STAT5 signaling regulated prostate epithelial cell hierarchy. Interestingly, ERK1/2 and AKT, but not STAT3 and androgen signaling, emerged as escape mechanisms leading to delayed tumor development in aged Pb-PRL^ΔSTAT5 mice. [Cancers] Full Article

A Novel FGFR3 Splice Variant Preferentially Expressed in African American Prostate Cancer Drives Aggressive Phenotypes and Docetaxel Resistance

Ectopic overexpression of FGFR3-S in European American prostate cancer cell lines led to enhanced receptor autophosphorylation and increased activation of the downstream signaling effectors AKT, STAT3, and ribosomal S6 compared to FGFR3-L. The increased oncogenic signaling imparted by FGFR3-S was associated with a substantial gain in proliferative and anti-apoptotic activities, as well as a modest but significant gain in cell motility. [Mol Cancer Res] Abstract

Circular RNA CircABCC4 as the ceRNA of miR-1182 Facilitates Prostate Cancer Progression by Promoting FOXP4 Expression

Researchers found that circABCC4 was remarkably up-regulated in prostate cancer tissues and cell lines and promoted FOXP4 expression by sponging miR-1182 in prostate cancer cells. CircABCC4 knockdown markedly suppressed prostate cancer cell proliferation, cell-cycle progression, migration and invasion in vitro. [J Cell Mol Med] Full Article

The Homeobox Gene, HOXB13, Regulates a Mitotic Protein-Kinase Interaction Network in Metastatic Prostate Cancers

HSPB8 mRNA expression was significantly increased following HOXB13 depletion in multiple metastatic castration-resistant prostate cancer (CRPC) models. Increased expression of HSPB8 by the microtubule inhibitor colchicine or by exogenous means suppressed migration of metastatic CRPC cells. [Sci Rep] Full Article

MicroRNA-214 Targets PTK6 to Inhibit Tumorigenic Potential and Increase Drug Sensitivity of Prostate Cancer Cells

Mechanistically, miR-214 inhibited prostate cancer cell proliferation by targeting protein tyrosine kinase 6 (PTK6). Restoration of PTK6 expression attenuated the inhibitory effect of miR-214 on cell proliferation. Moreover, simultaneous inhibition of PTK6 by ibrutinib and miR-214 significantly reduced cell proliferation/survival. [Sci Rep] Full Article

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Clonal Evolution and Epithelial Plasticity in the Emergence of AR-Independent Prostate Carcinoma

The authors discuss the switches between different cell fates that occur in response to AR blockade or acquisition of specific oncogenic mutations, such as those in TP53 and RB1, during the evolution to castration-resistant prostate cancer. They highlight the urgent need to dissect the mechanistic underpinnings of these transitions and identify novel vulnerabilities that can be targeted therapeutically. [Trends Cancer] Abstract

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TRACON Pharmaceuticals Provides Update on Phase I/II Trial of TRC253 in Patients with Metastatic Castrate Resistant Prostate Cancer

TRACON Pharmaceuticals provided an update on its TRC253 program for the treatment of metastatic castrate resistant prostate cancer, which was licensed from Janssen Pharmaceutica N.V. in 2016. TRC253 is a novel, orally bioavailable small molecule discovered and developed by Janssen that is a potent, high affinity competitive inhibitor of the AR. [TRACON Pharmaceuticals, Inc.] Press Release

Spring Bank Submits IND Application for SB 11285, an IV-Administered STING Agonist, for the Treatment of Advanced Solid Tumors

Spring Bank Pharmaceuticals, Inc. announced that it has submitted an Investigational New Drug (IND) application to the FDA for the company’s intravenously (IV)-administered stimulator of interferon gene (STING) agonist development candidate, SB 11285, to initiate a Phase I trial with the principal goals of evaluating safety, tolerability and initial anti-tumor activity in patients with advanced solid tumors. [Spring Bank Pharmaceuticals, Inc.] Press Release

Cybrexa Therapeutics Receives SBIR Grant to Support Development of Lead Candidate CBX-11 in Combination with Chemotherapy Agents

Cybrexa Therapeutics announced that the company has been awarded a Fast Track Small Business Innovation Research (SBIR) Grant from the National Institute of Health. This award will support the development of the company’s lead candidate, CBX-11, Cybrexa’s proprietary alphalex^™ technology combined with the already-approved oral small molecule poly ADP-ribose polymerase inhibitor rucaparib, in combination with chemotherapy. [Cybrexa Therapeutics (GlobeNewswire, Inc.)] Press Release

Mexican President Eases Up on Researchers’ Travel Rules

A month after announcing increased austerity measures on international travel for scientists, Mexico’s National Council of Science and Technology announced last month that at least one restriction would be loosened. Scientists would not require presidential approval for every trip abroad. [The Scientist] Editorial

Hungarian Law Wrests Control of Research from Scientific Academy

The Hungarian Parliament passed a bill that takes control for funding Hungarian research bodies away from the Hungarian Academy of Sciences and gives it to a government-led committee, Reuters reports. [The Scientist] Editorial

NEW EMBL Conference: Cancer Genomics
November 4-6, 2019
Heidelberg, Germany

Visit our events page to see a complete list of events in the community.

NEW Research Scientist – Prostate Cancer Progression & Resistance (MD Anderson Cancer Center)

NEW Postdoctoral Researchers – Inherited Genetics of Prostate & Testicular Cancer (Karolinska Institutet)

NEW Endowed Chair Faculty – Prostate Cancer (Cleveland Clinic Lerner College of Medicine of Case Western Reserve University)

Postdoctoral Position – Prostate Biology (University of Washington)

Postdoctoral Scientist – Prostate Organoids (Rutgers Cancer Institute of New Jersey)

Research Lab Specialist – Tumor Microenvironment & Cell Behavior (University of Southern California)

Postdoctoral Fellow – Jak-Stat Signaling in Prostate and Pancreatic Cancer (Medical College of Wisconsin)

Research Scientist – Cancer Cell Line Development (QLB Biotherapeutics, Inc.)

Postdoctoral Researcher – Neutrophils in Prostate and Pancreatic Cancer (University of Nebraska Medical Center)

Postdoctoral Fellow – Nanomedicine in Prostate Cancer (Queen’s University Belfast)

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