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4 results on '"Gallent B"'

1. The homeodomain regulates stable DNA binding of prostate cancer target ONECUT2.

Author

Chatterjee A, Gallent B, Katiki M, Qian C, Harter MR, Silletti S, Komives EA, Freeman MR, and Murali R

Subjects
Male, Humans, Cell Line, Tumor, Arginine metabolism, Arginine chemistry, Binding Sites, Gene Expression Regulation, Neoplastic, Animals, Prostatic Neoplasms metabolism, Prostatic Neoplasms genetics, Homeodomain Proteins metabolism, Homeodomain Proteins genetics, Homeodomain Proteins chemistry, DNA metabolism, DNA chemistry, Transcription Factors metabolism, Transcription Factors chemistry, Protein Binding
Abstract

The CUT and homeodomain are ubiquitous DNA binding elements often tandemly arranged in multiple transcription factor families. However, how the CUT and homeodomain work concertedly to bind DNA remains unknown. Using ONECUT2, a driver and therapeutic target of advanced prostate cancer, we show that while the CUT initiates DNA binding, the homeodomain thermodynamically stabilizes the ONECUT2-DNA complex through allosteric modulation of CUT. We identify an arginine pair in the ONECUT family homeodomain that can adapt to DNA sequence variations. Base interactions by this ONECUT family-specific arginine pair as well as the evolutionarily conserved residues are critical for optimal DNA binding and ONECUT2 transcriptional activity in a prostate cancer model. The evolutionarily conserved base interactions additionally determine the ONECUT2-DNA binding energetics. These findings provide insights into the cooperative DNA binding by CUT-homeodomain proteins., (© 2024. The Author(s).)

Published
2024
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2. ONECUT2 acts as a lineage plasticity driver in adenocarcinoma as well as neuroendocrine variants of prostate cancer.

Author

Qian C, Yang Q, Rotinen M, Huang R, Kim H, Gallent B, Yan Y, Cadaneanu RM, Zhang B, Kaochar S, Freedland SJ, Posadas EM, Ellis L, Di Vizio D, Morrissey C, Nelson PS, Brady L, Murali R, Campbell MJ, Yang W, Knudsen BS, Mostaghel EA, Ye H, Garraway IP, You S, and Freeman MR

Subjects
Male, Humans, Cell Line, Tumor, Phenylthiohydantoin pharmacology, Phenylthiohydantoin analogs & derivatives, Nerve Tissue Proteins genetics, Nerve Tissue Proteins metabolism, Epigenesis, Genetic, RNA-Binding Proteins metabolism, RNA-Binding Proteins genetics, Neuroendocrine Tumors genetics, Neuroendocrine Tumors pathology, Neuroendocrine Tumors metabolism, Neuroendocrine Tumors drug therapy, Animals, Cell Lineage genetics, Mice, Receptors, Androgen metabolism, Receptors, Androgen genetics, Adenocarcinoma genetics, Adenocarcinoma pathology, Adenocarcinoma metabolism, Adenocarcinoma drug therapy, Receptors, Glucocorticoid metabolism, Receptors, Glucocorticoid genetics, Prostatic Neoplasms genetics, Prostatic Neoplasms pathology, Prostatic Neoplasms metabolism, Prostatic Neoplasms drug therapy, Drug Resistance, Neoplasm genetics, Benzamides pharmacology, Nitriles pharmacology, Gene Expression Regulation, Neoplastic
Abstract

Androgen receptor- (AR-) indifference is a mechanism of resistance to hormonal therapy in prostate cancer (PC). Here we demonstrate that ONECUT2 (OC2) activates resistance through multiple drivers associated with adenocarcinoma, stem-like and neuroendocrine (NE) variants. Direct OC2 gene targets include the glucocorticoid receptor (GR; NR3C1) and the NE splicing factor SRRM4, which are key drivers of lineage plasticity. Thus, OC2, despite its previously described NEPC driver function, can indirectly activate a portion of the AR cistrome through epigenetic activation of GR. Mechanisms by which OC2 regulates gene expression include promoter binding, enhancement of genome-wide chromatin accessibility, and super-enhancer reprogramming. Pharmacologic inhibition of OC2 suppresses lineage plasticity reprogramming induced by the AR signaling inhibitor enzalutamide. These results demonstrate that OC2 activation promotes a range of drug resistance mechanisms associated with treatment-emergent lineage variation in PC and support enhanced efforts to therapeutically target OC2 as a means of suppressing treatment-resistant disease., (© The Author(s) 2024. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Published
2024
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3. ONECUT2 Activates Diverse Resistance Drivers of Androgen Receptor-Independent Heterogeneity in Prostate Cancer.

Author

Qian C, Yang Q, Rotinen M, Huang R, Kim H, Gallent B, Yan Y, Cadaneanu RM, Zhang B, Kaochar S, Freedland SJ, Posadas EM, Ellis L, Vizio DD, Morrissey C, Nelson PS, Brady L, Murali R, Campbell MJ, Yang W, Knudsen BS, Mostaghel EA, Ye H, Garraway IP, You S, and Freeman MR

Abstract

Androgen receptor- (AR-) indifference is a mechanism of resistance to hormonal therapy in prostate cancer (PC). Here we demonstrate that the HOX/CUT transcription factor ONECUT2 (OC2) activates resistance through multiple drivers associated with adenocarcinoma, stem-like and neuroendocrine (NE) variants. Direct OC2 targets include the glucocorticoid receptor and the NE splicing factor SRRM4 , among others. OC2 regulates gene expression by promoter binding, enhancement of chromatin accessibility, and formation of novel super-enhancers. OC2 also activates glucuronidation genes that irreversibly disable androgen, thereby evoking phenotypic heterogeneity indirectly by hormone depletion. Pharmacologic inhibition of OC2 suppresses lineage plasticity reprogramming induced by the AR signaling inhibitor enzalutamide. These results demonstrate that OC2 activation promotes a range of drug resistance mechanisms associated with treatment-emergent lineage variation in PC. Our findings support enhanced efforts to therapeutically target this protein as a means of suppressing treatment-resistant disease.

Published
2023
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4. The homeodomain drives favorable DNA binding energetics of prostate cancer target ONECUT2.

Author

Chatterjee A, Gallent B, Katiki M, Qian C, Harter MR, Freeman MR, and Murali R

Abstract

The ONECUT transcription factors feature a CUT and a homeodomain, evolutionarily conserved elements that bind DNA cooperatively, but the process remains mechanistically enigmatic. Using an integrative DNA binding analysis of ONECUT2, a driver of aggressive prostate cancer, we show that the homeodomain energetically stabilizes the ONECUT2-DNA complex through allosteric modulation of CUT. Further, evolutionarily conserved base-interactions in both the CUT and homeodomain are necessary for the favorable thermodynamics. We have identified a novel arginine pair unique to the ONECUT family homeodomain that can adapt to DNA sequence variations. Base interactions in general, including by this arginine pair, are critical for optimal DNA binding and transcription in a prostate cancer model. These findings provide fundamental insights into DNA binding by CUT-homeodomain proteins with potential therapeutic implications., One-Sentence Summary: Base-specific interactions regulate homeodomain-mediated stabilization of DNA binding by the ONECUT2 transcription factor.

Published
2023
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