PD07-09 MEIS PROTEINS INHIBIT HOXB13-DEPENDENT PROSTATE CANCER METASTASIS AND ANDROGEN RECEPTOR SIGNALING

Abstract

You have accessJournal of UrologyCME1 May 2022PD07-09 MEIS PROTEINS INHIBIT HOXB13-DEPENDENT PROSTATE CANCER METASTASIS AND ANDROGEN RECEPTOR SIGNALING Srikanth Perike, Calvin VanOpstall, Mathias Morales, Sophia Lamperis, Steve Kregel, Ryan Brown, and Donald J. Vander Griend Srikanth PerikeSrikanth Perike More articles by this author , Calvin VanOpstallCalvin VanOpstall More articles by this author , Mathias MoralesMathias Morales More articles by this author , Sophia LamperisSophia Lamperis More articles by this author , Steve KregelSteve Kregel More articles by this author , Ryan BrownRyan Brown More articles by this author , and Donald J. Vander GriendDonald J. Vander Griend More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002526.09AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Prostate cancer (PCa) is one of the most frequently diagnosed malignancies in men, and its incidence and mortality continue to be a significant clinical problem. Recent evidence from our lab identified MEIS1, an important HOX protein cofactor, as a potential tumor suppressor. Patients bearing MEIS1-positive prostate tumors were significantly less likely to have biochemical recurrence and metastasis compared to men bearing MEIS-negative tumors. Androgen receptor (AR), the major oncogene in PCa, has been shown to interact with HOXB13 to promote prostate cancer progression, but the function of MEIS proteins to antagonize AR/HOXB13 interactions are unknown. We hypothesize that MEIS1 proteins interact with HOXB13 to suppress cancer initiation and progression, and loss of MEIS1 expression in a portion of prostate tumors enables oncogenic AR/HOXB13 interactions. METHODS: We determined the impact of MEIS1 expression and dependency of HOXB13 on AR signaling using cell lines ectopically expressing MEIS1 and/or CRISPR-mediated HOXB13 deletion in both androgen-sensitive LAPC4 and castration-resistant CWR22Rv1 cells. Western blots, qPCR, Proximity Ligation Assay and co-IPs were performed to evaluate the relationship between expression of MEIS1, HOXB13 and AR. Hormonally-intact and castrated male nude mice were used to test the in vivo capability of MEIS1-mediated tumor xenograft formation and rate of tumor growth in the presence and absence of AR ligand. RNA sequencing and informatics analyses was performed on tumor xenografts to determine the global impact of MEIS expression on AR gene targeting in PCa. RESULTS: We found that AR expression was significantly increased when MEIS1 was ectopically expressed compared to controls and HOXB13 knock-out lines. Re-expression of MEIS1 enhanced the binding between HOXB13-MEIS and AR-MEIS, and reduced AR-HOXB13 interaction. In castrated mice, re-expression of MEIS1 significantly decreased the tumor formation and tumor growth rate compared to hormonally intact nude mice. Conversely, xenografts of HOXB13-knockout tumors showed an increased rate of tumor growth and tumor formation compared to MEIS1-expressing cells and controls in both hormonally intact and castrated nude mice. Our preliminary RNA-Seq analysis demonstrate that when MEIS is present, AR pathway activation in response to androgen was associated with increased differentiation and growth suppression. CONCLUSIONS: Our collective data supports our hypothesis that increased MEIS1 expression reduces the AR/HOXB13 interaction and increases the in vivo sensitivity to host castration; this suggests that MEIS-positive cells have decreased oncogenic AR signaling. Future RNA-Seq studies combined with AR ChIP-Seq data will enable us to identify the MEIS-AR targeted genes that are involved in AR pathway modulation that inhibit prostate cancer cell proliferation and suppress tumor progression. These data provide us a strong rationale to support the potential utility of MEIS proteins as predictive clinical biomarkers of metastatic progression. Source of Funding: Funding: This work was supported by the Urology Care Foundation Research Scholar Award sponsored by Chesapeake Urology Associates, DOD grant PC130587, and DOD grant PC180414 © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e102 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Srikanth Perike More articles by this author Calvin VanOpstall More articles by this author Mathias Morales More articles by this author Sophia Lamperis More articles by this author Steve Kregel More articles by this author Ryan Brown More articles by this author Donald J. Vander Griend More articles by this author Expand All Advertisement PDF DownloadLoading ...