Research Project: Sürekli Aktif Androjen Reseptörü Varyantlarının Karakterizasyonu
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Contributors
Funders
ID
TB.00203
Authors
Lack, Nathan Alan
Faculty Member
Publications
Increased nuclear factor I-mediated chromatin access drives transition to androgen receptor splice variant dependence in prostate cancer
(Elsevier B.V., 2024) Lack, Nathan Alan; Poluben, L; Nouri, M; Liang, JQ; Chen, SY; Varkaris, A; Ersoy-Fazlioglu, B; Voznesensky, O; Lee, II; Qiu, XT; Cato, L; Seo, JH; Freedman, ML; Sowalsky, AG; Corey, E; Nelson, PS; Brown, M; Long, HW; Russo, JW; Balk, SP; School of Medicine; Yes; SCHOOL OF MEDICINE
Androgen receptor (AR) splice variants, of which ARv7 is the most common, are increased in castration-resistant prostate cancer, but the extent to which they drive AR activity is unclear. We generated a subline of VCaP cells (VCaP16) that is resistant to the AR inhibitor enzalutamide (ENZ). AR activity in VCaP16 is driven by ARv7, independently of full-length AR (ARfl), and its cistrome and transcriptome mirror those of ARfl in VCaP cells. ARv7 expression increases rapidly in response to ENZ, but there is a delay in gaining chromatin binding and transcriptional activity, which is associated with increased chromatin accessibility. AR and nuclear factor I (NFI) motifs are most enriched at more accessible sites, and NFIB/X knockdown greatly diminishes ARv7 function. These findings indicate that ARv7 can drive the AR program but that its activity is dependent on adaptations that increase chromatin accessibility to enhance its intrinsically weak chromatin binding.
DNA binding alters ARv7 dimer interactions
(Company of Biologists, 2021) Özgün, Fatma; Kaya, Zeynep; Lack, Nathan Alan; Morova, Tunç; Geverts, Bart; Abraham, Tsion E.; Houtsmuller, Adriaan B.; van Royen, Martin E.; KUTTAM (Koç University Research Center for Translational Medicine); Graduate School of Sciences and Engineering; School of Medicine; Yes; GRADUATE SCHOOL OF SCIENCES AND ENGINEERING; Research Center; SCHOOL OF MEDICINE
Androgen receptor (AR) splice variants are proposed to be a potential driver of lethal castration-resistant prostate cancer. AR splice variant 7 (ARv7) is the most commonly observed isoform and strongly correlates with resistance to second-generation anti-androgens. Despite this clinical evidence, the interplay between ARv7 and the highly expressed full-length AR (ARfl) remains unclear. In this work, we show that ARfl/ARv7 heterodimers readily form in the nucleus via an intermolecular N/C interaction that brings the four termini of the proteins in close proximity. Combining fluorescence resonance energy transfer and fluorescence recovery after photobleaching, we demonstrate that these heterodimers undergo conformational changes following DNA binding, indicating dynamic nuclear receptor interaction. Although transcriptionally active, ARv7 can only form short-term interactions with DNA at highly accessible high-occupancy ARfl binding sites. Dimerization with ARfl does not affect ARv7 binding dynamics, suggesting that DNA binding occupancy is determined by the individual protein monomers and not the homodimer or heterodimer complex. Overall, these biophysical studies reveal detailed properties of ARv7 dynamics as both a homodimer or heterodimer with ARfl.
