Abstract 3441
Background
Resistance to androgen receptor signaling is arguably the principal hallmark of lethal prostate cancer. Several mechanisms account for this resistance, including mutations in the AR, restoration of signaling downstream of the pharmacological blocking and activation of alternative oncogenic pathways.
Methods
We used the Nkx3.1CreERT2/+; Ptenfloxed/floxed; p53floxed/floxed (NPp53) mice that develop CRPC upon castration and undergo neuroendocrine differentiation with anti-AR treatment to isolate Enzalutamide resistance prostate cancer cells.
Results
Recently, we showed that activation of the chromatin remodeler Nsd2 is required for PCa metastasis and is strongly associated to tumor progression, and that its silencing markedly reduced the metastatic burden and increased survival. Our current data indicates that Nsd2 silencing sensitizes PCa cells to anti-AR treatment. Nsd2 KO using CRISPR/Cas9 resulted in a markedly enhanced efficacy of Enzalutamide and a significant reduction of AR transcriptional activity with either Enzalutamide or Abiraterone using two different reporter assays. Next, To identify Nsd2-dependent AR co-regulators we immunoprecipitated chromatin-bound endogenous AR in NPp53 cells and NPp53-Nsd2KO and performed nano-LC-MS/MS mass spectrometry on the purified peptide mix. In particular, data indicates that AR association with SWI/SNF members is stronger in the absence of Nsd2, suggesting that Nsd2 overexpression might impair AR interaction to the SWI/SNF complex. We next tested whether Nsd2 in fact binds SWI/SNF subunits by co-immunoprecipitation in the NPp53 cells and whether BAF155, BAF170 and BRG1 association to AR increases in the absence of Nsd2. As suspected, there is a remarkable increase in the binding of AR to SWI/SNF subunits BAF155, BAF170 and BRG1 in the absence of Nsd2.
Conclusions
Together, our data suggests that the mechanisms by which Nsd2 overexpression drives aggressive castration resistant and androgen independent PCa may be in part through destabilizing the AR-SWI/SNF interaction and altering the specificity of the AR cistrome. Ongoing work will further elucidate this by analyzing chromatin accessibility data coupled with transcriptomics and ChIPseq data for the AR and the BAF170, BAF155 and Brg1 SWI/SNF subunits.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Alvaro Aytes.
Funding
EAU.
Disclosure
All authors have declared no conflicts of interest.
Resources from the same session
3088 - Spanish Survey of treatment recommendations for elderley patients with glioblastoma
Presenter: María Ángeles Vaz Salgado
Session: Poster Display session 1
Resources:
Abstract
3484 - Updated analysis of the National Registry of Nervous System Tumors in Spain (RETSINE). RETSINE: National Registry of Nervous System Tumors of the Spanish Research Group in Neuro-oncology (GEINO) and Spanish Infrequent and Orphan Tumors Group (GETHI)
Presenter: Isaac Ceballos Lenza
Session: Poster Display session 1
Resources:
Abstract
4737 - Development and validation of novel nomograms predicting survival of malignant ependymoma patients: A population-based study
Presenter: Alzhraa Abbas
Session: Poster Display session 1
Resources:
Abstract
4740 - Characteristics, incidence, and survival of primary cerebral lymphoma: A population based study
Presenter: Sherief Ghozy
Session: Poster Display session 1
Resources:
Abstract
5362 - Trends in Incidence and Survival Analyses of Adult-onset Medulloblastoma
Presenter: Feifei Lin
Session: Poster Display session 1
Resources:
Abstract
3868 - Meta of classical chemotherapy compared with high-dose chemotherapy combined with autologous stem cell transplantation in newly diagnosed medulloblastoma patients after radiotherapy
Presenter: Mengting Zhang
Session: Poster Display session 1
Resources:
Abstract
4446 - Effect of cumulative dose of maintenance temozolomide on overall survival in patients with high grade glia tumors: a single institution analysis
Presenter: Marta Nerone
Session: Poster Display session 1
Resources:
Abstract
5119 - Markers of systemic inflammation correlate with survival prognosis in patients with newly diagnosed brain metastases
Presenter: Angelika Starzer
Session: Poster Display session 1
Resources:
Abstract
3882 - Venous Thromboembolism and Intracranial Hemorrhage in Patients with High-grade Glioma
Presenter: Clara Borges
Session: Poster Display session 1
Resources:
Abstract
5152 - Comprehensive Geriatric Assessment (CGA) can categorize elderly glioblastoma (GBM) patients into three groups predicting survival: a monoinstitutional study
Presenter: Eleonora Bergo
Session: Poster Display session 1
Resources:
Abstract