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1.
Cell ; 174(5): 1200-1215.e20, 2018 08 23.
Artigo em Inglês | MEDLINE | ID: mdl-30100187

RESUMO

Nuclear pore complexes (NPCs) regulate nuclear-cytoplasmic transport, transcription, and genome integrity in eukaryotic cells. However, their functional roles in cancer remain poorly understood. We interrogated the evolutionary transcriptomic landscape of NPC components, nucleoporins (Nups), from primary to advanced metastatic human prostate cancer (PC). Focused loss-of-function genetic screen of top-upregulated Nups in aggressive PC models identified POM121 as a key contributor to PC aggressiveness. Mechanistically, POM121 promoted PC progression by enhancing importin-dependent nuclear transport of key oncogenic (E2F1, MYC) and PC-specific (AR-GATA2) transcription factors, uncovering a pharmacologically targetable axis that, when inhibited, decreased tumor growth, restored standard therapy efficacy, and improved survival in patient-derived pre-clinical models. Our studies molecularly establish a role of NPCs in PC progression and give a rationale for NPC-regulated nuclear import targeting as a therapeutic strategy for lethal PC. These findings may have implications for understanding how NPC deregulation contributes to the pathogenesis of other tumor types.


Assuntos
Fator de Transcrição E2F1/metabolismo , Glicoproteínas de Membrana/metabolismo , Poro Nuclear/fisiologia , Neoplasias da Próstata/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo , Fatores de Transcrição/metabolismo , Transporte Ativo do Núcleo Celular , Carcinogênese , Núcleo Celular/metabolismo , Proliferação de Células , Fator de Transcrição GATA2/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Membrana Nuclear , Complexo de Proteínas Formadoras de Poros Nucleares , Transdução de Sinais
2.
EMBO J ; 40(16): e102509, 2021 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-34155658

RESUMO

The SAGA coactivator complex is essential for eukaryotic transcription and comprises four distinct modules, one of which contains the ubiquitin hydrolase USP22. In yeast, the USP22 ortholog deubiquitylates H2B, resulting in Pol II Ser2 phosphorylation and subsequent transcriptional elongation. In contrast to this H2B-associated role in transcription, we report here that human USP22 contributes to the early stages of stimulus-responsive transcription, where USP22 is required for pre-initiation complex (PIC) stability. Specifically, USP22 maintains long-range enhancer-promoter contacts and controls loading of Mediator tail and general transcription factors (GTFs) onto promoters, with Mediator core recruitment being USP22-independent. In addition, we identify Mediator tail subunits MED16 and MED24 and the Pol II subunit RBP1 as potential non-histone substrates of USP22. Overall, these findings define a role for human SAGA within the earliest steps of transcription.


Assuntos
Ubiquitina Tiolesterase/genética , Apoptose , Estresse do Retículo Endoplasmático/genética , Células HCT116 , Humanos , Complexo Mediador/genética , Regiões Promotoras Genéticas , RNA Polimerase II , Transcrição Gênica
3.
Br J Cancer ; 130(1): 53-62, 2024 01.
Artigo em Inglês | MEDLINE | ID: mdl-37980367

RESUMO

BACKGROUND: CC-115, a dual mTORC1/2 and DNA-PK inhibitor, has promising antitumour activity when combined with androgen receptor (AR) inhibition in pre-clinical models. METHODS: Phase 1b multicentre trial evaluating enzalutamide with escalating doses of CC-115 in AR inhibitor-naive mCRPC patients (n = 41). Primary endpoints were safety and RP2D. Secondary endpoints included PSA response, time-to-PSA progression, and radiographic progression. RESULTS: Common adverse effects included rash (31.7% Grades 1-2 (Gr); 31.7% Gr 3), pruritis (43.9% Gr 1-2), diarrhoea (37% Gr 1-2), and hypertension (17% Gr 1-2; 9.8% Gr 3). CC-115 RP2D was 5 mg twice a day. In 40 evaluable patients, 80% achieved ≥50% reduction in PSA (PSA50), and 58% achieved ≥90% reduction in PSA (PSA90) by 12 weeks. Median time-to-PSA progression was 14.7 months and median rPFS was 22.1 months. Stratification by PI3K alterations demonstrated a non-statistically significant trend towards improved PSA50 response (PSA50 of 94% vs. 67%, p = 0.08). Exploratory pre-clinical analysis suggested CC-115 inhibited mTOR pathway strongly, but may be insufficient to inhibit DNA-PK at RP2D. CONCLUSIONS: The combination of enzalutamide and CC-115 was well tolerated. A non-statistically significant trend towards improved PSA response was observed in patients harbouring PI3K pathway alterations, suggesting potential predictive biomarkers of response to a PI3K/AKT/mTOR pathway inhibitor. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02833883.


Assuntos
Benzamidas , Feniltioidantoína , Neoplasias de Próstata Resistentes à Castração , Pirazinas , Triazóis , Masculino , Humanos , Neoplasias de Próstata Resistentes à Castração/patologia , Antígeno Prostático Específico/uso terapêutico , Alvo Mecanístico do Complexo 1 de Rapamicina , Fosfatidilinositol 3-Quinases , Nitrilas/uso terapêutico , DNA/uso terapêutico
4.
J Surg Oncol ; 128(6): 931-937, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37818915

RESUMO

Gaps in the cancer care continuum are vast, both in the United States and globally. The American Cancer Society orchestrates an integrated, tripartite approach toward improving the lives of cancer patients and their families through research, advocacy, and patient support. With a focus on eradicating cancer disparities, the American Cancer Society aims to scale and deploy best practices worldwide through partnerships, to ensure everyone has an opportunity to prevent, detect, treat, and survive cancer.


Assuntos
Neoplasias , Humanos , Estados Unidos , American Cancer Society , Neoplasias/prevenção & controle , Neoplasias/diagnóstico
5.
Mol Cell ; 58(6): 925-34, 2015 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-26091341

RESUMO

Poly(ADP-ribose) polymerase 1 (PARP1) inhibitors were recently shown to have potential clinical impact in a number of disease settings, particularly as related to cancer therapy, treatment for cardiovascular dysfunction, and suppression of inflammation. The molecular basis for PARP1 inhibitor function is complex, and appears to depend on the dual roles of PARP1 in DNA damage repair and transcriptional regulation. Here, the mechanisms by which PARP-1 inhibitors elicit clinical response are discussed, and strategies for translating the preclinical elucidation of PARP-1 function into advances in disease management are reviewed.


Assuntos
Cromatina/genética , Reparo do DNA , Poli(ADP-Ribose) Polimerases/metabolismo , Transcrição Gênica , Inibidores Enzimáticos/uso terapêutico , Humanos , Terapia de Alvo Molecular/métodos , Terapia de Alvo Molecular/tendências , Neoplasias/tratamento farmacológico , Neoplasias/genética , Poli(ADP-Ribose) Polimerase-1 , Inibidores de Poli(ADP-Ribose) Polimerases , Pesquisa Translacional Biomédica/métodos , Pesquisa Translacional Biomédica/tendências
6.
Cancer ; 128 Suppl 13: 2673-2677, 2022 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-35699608

RESUMO

Over the past 30 years, the American Cancer Society (ACS) has played a key role in shaping the field of patient navigation as a means to address cancer disparities. Through collaborations with organizations like the National Navigation Roundtable and the ACS Cancer Action Network, the ACS is uniquely positioned to help develop sustainable navigation models that directly address disparities in access to quality cancer care. As health systems continue to adapt and change in response to various factors, including an aging population and rapid advances in screening and treatment, it is important to evaluate existing navigation-delivery models and promote those that are sustainable while maximizing reach and impact and providing the greatest return on investment (ROI). In this report, the term ROI is used to describe the potential financial gain resulting from the navigation service (ROI = net gains/total program cost). Calculating net gains requires assigning a monetary value to key outcomes and subtracting this amount from the total program cost. ROI is a measure often used by health care executives to show the savings or financial benefit from a program or service. Other measures of financial impact exist that may be of greater or lesser value to program leadership, including cost effectiveness (if financial information for outcomes is not available) and cost-benefit analysis. Here, the current and future commitment of the ACS to advancing the field of patient navigation is outlined as an organizational priority and a key building block in their health equity strategy. By working with partners like the National Navigation Roundtable, the ACS can help guide efforts to evaluate these approaches, with the goal of identifying the most effective and potentially sustainable models of delivery while also increasing equitable access to care.


Assuntos
Neoplasias , Navegação de Pacientes , Idoso , American Cancer Society , Análise Custo-Benefício , Atenção à Saúde , Humanos , Neoplasias/terapia
7.
Proc Natl Acad Sci U S A ; 115(40): E9298-E9307, 2018 10 02.
Artigo em Inglês | MEDLINE | ID: mdl-30224477

RESUMO

Overexpression of the deubiquitylase ubiquitin-specific peptidase 22 (USP22) is a marker of aggressive cancer phenotypes like metastasis, therapy resistance, and poor survival. Functionally, this overexpression of USP22 actively contributes to tumorigenesis, as USP22 depletion blocks cancer cell cycle progression in vitro, and inhibits tumor progression in animal models of lung, breast, bladder, ovarian, and liver cancer, among others. Current models suggest that USP22 mediates these biological effects via its role in epigenetic regulation as a subunit of the Spt-Ada-Gcn5-acetyltransferase (SAGA) transcriptional cofactor complex. Challenging the dogma, we report here a nontranscriptional role for USP22 via a direct effect on the core cell cycle machinery: that is, the deubiquitylation of the G1 cyclin D1 (CCND1). Deubiquitylation by USP22 protects CCND1 from proteasome-mediated degradation and occurs separately from the canonical phosphorylation/ubiquitylation mechanism previously shown to regulate CCND1 stability. We demonstrate that control of CCND1 is a key mechanism by which USP22 mediates its known role in cell cycle progression. Finally, USP22 and CCND1 levels correlate in patient lung and colorectal cancer samples and our preclinical studies indicate that targeting USP22 in combination with CDK inhibitors may offer an approach for treating cancer patients whose tumors exhibit elevated CCND1.


Assuntos
Neoplasias Colorretais/metabolismo , Ciclina D1/metabolismo , Epigênese Genética , Fase G1 , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares/metabolismo , Proteólise , Tioléster Hidrolases/metabolismo , Ubiquitinação , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Ciclina D1/genética , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Células MCF-7 , Estabilidade Proteica , Tioléster Hidrolases/genética , Ubiquitina Tiolesterase
8.
Int J Cancer ; 146(7): 2047-2058, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-31732968

RESUMO

More than one-third of patients with locally advanced cervical cancer do not respond to chemoradiation therapy (CRT). We aimed to characterize the transcriptional landscape of paired human cervical tumors before and during CRT in order to gain insight into the evolution of treatment response and to elucidate mechanisms of treatment resistance. We prospectively collected cervical tumor biopsies from 115 patients both before and 3 weeks into CRT. RNA-sequencing, Gene Set Enrichment Analysis and HPV gene expression were performed on 20 paired samples that had adequate neoplastic tissue mid-treatment. Tumors from patients with no evidence of disease (NED) at last follow-up had enrichment in pathways related to the immune response both pretreatment and mid-treatment, while tumors from patients dead of disease (DOD) demonstrated enrichment in biosynthetic and mitotic pathways but not in immune-related pathways. Patients DOD had decreased expression of T-cell and cytolytic genes and increased expression of PD-L2 mid-treatment compared to patients NED. Histological and immunohistochemical analysis revealed a decrease in tumor-associated lymphocytes (TAL) during CRT in all patients but tumors from patients DOD had a significantly more pronounced decrease in TALs and CD8+ cells mid-treatment, which was validated in a larger mid-treatment cohort. Finally, patients DOD retained more HPV E6/E7 gene expression during CRT and this was associated with increased expression of genes driving mitosis, which was corroborated in vitro. Our results suggest that decreased local immune response and retained HPV gene expression may be acting together to promote treatment resistance during CRT in patients with cervical cancer.


Assuntos
Resistencia a Medicamentos Antineoplásicos , Regulação Viral da Expressão Gênica , Imunomodulação/efeitos dos fármacos , Papillomaviridae/genética , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/virologia , Neoplasias do Colo do Útero/etiologia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biópsia , Terapia Combinada , Resistencia a Medicamentos Antineoplásicos/imunologia , Feminino , Perfilação da Expressão Gênica , Humanos , Metástase Linfática , Estadiamento de Neoplasias , Papillomaviridae/classificação , Papillomaviridae/imunologia , Infecções por Papillomavirus/imunologia , Prognóstico , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Neoplasias do Colo do Útero/diagnóstico , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/mortalidade
9.
Int J Cancer ; 144(5): 1151-1159, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30288742

RESUMO

A plethora of individual candidate biomarkers for predicting biochemical relapse in localized prostate cancer (PCa) have been proposed. Combined biomarkers may improve prognostication, and ensuring validation against more clinically relevant endpoints are required. The Australian PCa Research Centre NSW has contributed to numerous studies of molecular biomarkers associated with biochemical relapse. In the current study, these biomarkers were re-analyzed for biochemical relapse, metastatic relapse and PCa death with extended follow-up. Biomarkers of significance were then used to develop a combined prognostic model for clinical outcomes and validated in a large independent cohort. The discovery cohort (n = 324) was based on 12 biomarkers with a median follow-up of 16 years. Seven biomarkers were significantly associated with biochemical relapse. Three biomarkers were associated with metastases: AZGP1, Ki67 and PML. Only AZGP1 was associated with PCa death. In their individual and combinational forms, AZGP1 and Ki67 as a dual BM signature was the most robust predictor of metastatic relapse (AUC 0.762). The AZPG1 and Ki67 signature was validated in an independent cohort of 347 PCa patients. The dual BM signature of AZGP1 and Ki67 predicted metastasis in the univariable (HR 7.2, 95% CI, 1.6-32; p = 0.01) and multivariable analysis (HR 5.4, 95% CI, 1.2-25; p = 0.03). The dual biomarker signature marginally improved risk prediction compared to AZGP1 alone (AUC 0.758 versus 0.738, p < 0.001). Our findings indicate that biochemical relapse is not an adequate surrogate for metastasis or PCa death. The dual biomarker signature of AZGP1 and Ki67 offers a small benefit in predicting metastasis over AZGP1 alone.


Assuntos
Biomarcadores Tumorais/metabolismo , Metástase Neoplásica/patologia , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Austrália , Estudos de Coortes , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/patologia , Prognóstico , Próstata/metabolismo , Próstata/patologia , Prostatectomia/métodos , Neoplasias da Próstata/cirurgia
10.
Prostate ; 79(4): 333-339, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30450585

RESUMO

BACKGROUND: Genetic testing capability and guidelines are rapidly expanding to assess inherited prostate cancer (PCA). Clinical genetic data from multigene testing can provide insights into the germline pathogenic variant (PV) spectrum and correlates in men with PCA unselected for metastatic disease to optimize identification of men for genetic evaluation and management. METHODS: A retrospective cross-sectional analysis was conducted of de-identified clinical genetic testing data from a large commercial genetic testing laboratory in the US. ICD-10 claims codes were used to identify men with PCA, along with family history data. Gleason score was abstracted from test request forms. Overall PV rate among men with PCA was estimated, along with PVs in DNA repair genes. Family history and Gleason score association to germline DNA repair PVs was assessed using Fisher's exact test with correction for false-discovery. RESULTS: As of August 2017, genetic results were available on 1328 men with PCA. Overall PV rate was 15.6%, with 10.9% of PV in DNA repair genes. PVs were most commonly identified in BRCA2 (4.5%), CHEK2 (2.2%), ATM (1.8%), and BRCA1 (1.1%). Breast cancer family history was significantly associated with germline DNA repair PVs (OR 1.89, [95%CI 1.33, 2.68], P = 0.003). Among men with Gleason score>= 6 (n = 706), Gleason> = 8 was significantly associated with DNA repair PVs (OR 1.85 [95%CI 1.22, 2.80], P = 0.004). CONCLUSIONS: A substantial proportion of men with PCA unselected for metastatic disease carry germline DNA repair PVs. Breast cancer family history and high Gleason score are important predictors to identify men with PCA who may carry germline DNA repair PVs. Our findings support current NCCN guidelines and have implications for genetic assessment, therapeutic management, and cascade testing for men with PCA and their families.


Assuntos
Reparo do DNA/genética , Testes Genéticos/métodos , Células Germinativas/química , Neoplasias da Próstata/genética , Neoplasias da Próstata/terapia , Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/genética , Estudos Transversais , Feminino , Variação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Neoplasias da Próstata/patologia , Estudos Retrospectivos
11.
Can J Urol ; 26(5 Suppl 2): 22-23, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31629421

RESUMO

Despite significant advances in understanding the biology of advanced prostate cancer and approval of novel therapeutic agents, there is no durable cure for metastatic disease. Recent findings unmasked the importance of androgen receptor (AR) signaling in regulation of DNA repair, and alterations of the AR-DNA repair factor axis were shown to promote aggressive phenotypes including metastasis. These and related findings underscore the importance of determining impact AR-DNA repair factor alterations on prostate cancer progression.


Assuntos
Reparo do DNA/fisiologia , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Receptores Androgênicos/fisiologia , Humanos , Masculino , Transdução de Sinais
12.
Can J Urol ; 26(5 Suppl 2): 1-4, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31629412

RESUMO

In 2017 the Sidney Kimmel Cancer Center of Thomas Jefferson University held the first international consensus conference on the role of genetic testing for inherited prostate cancer risk. This article outlines the key elements of our 2017 consensus meeting and discusses the rationale and design of our follow up 2019 Philadelphia Prostate Cancer Consensus titled the 'Implementation of Genetic Testing for Inherited Prostate Cancer.'


Assuntos
Testes Genéticos , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/genética , Conferências de Consenso como Assunto , Humanos , Masculino
13.
N Engl J Med ; 373(18): 1697-708, 2015 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-26510020

RESUMO

BACKGROUND: Prostate cancer is a heterogeneous disease, but current treatments are not based on molecular stratification. We hypothesized that metastatic, castration-resistant prostate cancers with DNA-repair defects would respond to poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibition with olaparib. METHODS: We conducted a phase 2 trial in which patients with metastatic, castration-resistant prostate cancer were treated with olaparib tablets at a dose of 400 mg twice a day. The primary end point was the response rate, defined either as an objective response according to Response Evaluation Criteria in Solid Tumors, version 1.1, or as a reduction of at least 50% in the prostate-specific antigen level or a confirmed reduction in the circulating tumor-cell count from 5 or more cells per 7.5 ml of blood to less than 5 cells per 7.5 ml. Targeted next-generation sequencing, exome and transcriptome analysis, and digital polymerase-chain-reaction testing were performed on samples from mandated tumor biopsies. RESULTS: Overall, 50 patients were enrolled; all had received prior treatment with docetaxel, 49 (98%) had received abiraterone or enzalutamide, and 29 (58%) had received cabazitaxel. Sixteen of 49 patients who could be evaluated had a response (33%; 95% confidence interval, 20 to 48), with 12 patients receiving the study treatment for more than 6 months. Next-generation sequencing identified homozygous deletions, deleterious mutations, or both in DNA-repair genes--including BRCA1/2, ATM, Fanconi's anemia genes, and CHEK2--in 16 of 49 patients who could be evaluated (33%). Of these 16 patients, 14 (88%) had a response to olaparib, including all 7 patients with BRCA2 loss (4 with biallelic somatic loss, and 3 with germline mutations) and 4 of 5 with ATM aberrations. The specificity of the biomarker suite was 94%. Anemia (in 10 of the 50 patients [20%]) and fatigue (in 6 [12%]) were the most common grade 3 or 4 adverse events, findings that are consistent with previous studies of olaparib. CONCLUSIONS: Treatment with the PARP inhibitor olaparib in patients whose prostate cancers were no longer responding to standard treatments and who had defects in DNA-repair genes led to a high response rate. (Funded by Cancer Research UK and others; ClinicalTrials.gov number, NCT01682772; Cancer Research UK number, CRUK/11/029.).


Assuntos
Antineoplásicos/uso terapêutico , Reparo do DNA , Inibidores Enzimáticos/uso terapêutico , Ftalazinas/uso terapêutico , Piperazinas/uso terapêutico , Inibidores de Poli(ADP-Ribose) Polimerases , Neoplasias da Próstata/tratamento farmacológico , Adulto , Idoso , Anemia/induzido quimicamente , Proteínas Mutadas de Ataxia Telangiectasia/genética , Reparo do DNA/genética , Resistencia a Medicamentos Antineoplásicos , Inibidores Enzimáticos/efeitos adversos , Fadiga/induzido quimicamente , Genes BRCA2 , Genes Supressores de Tumor , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Metástase Neoplásica/tratamento farmacológico , Ftalazinas/efeitos adversos , Piperazinas/efeitos adversos , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia
14.
Mol Pharm ; 15(5): 1778-1790, 2018 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-29616555

RESUMO

Second generation antiandrogens have improved overall survival for men with metastatic castrate resistant prostate cancer; however, the antiandrogens result in suppression of androgen receptor (AR) activity in all tissues resulting in dose limiting toxicity. We sought to overcome this limitation through encapsulation in a prostate specific membrane antigen (PSMA)-conjugated nanoparticle. We designed and characterized a novel nanoparticle containing an antiandrogen, enzalutamide. Selectivity and enhanced efficacy was achieved through coating the particle with PSMA. The PSMA-conjugated nanoparticle was internalized selectively in AR expressing prostate cancer cells. It did not elicit an inflammatory effect. The efficacy of enzalutamide was not compromised through insertion into the nanoparticle; in fact, lower systemic drug concentrations of enzalutamide resulted in comparable clinical activity. Normal muscle cells were not impacted by the PSMA-conjugated containing antiandrogen. This approach represents a novel strategy to increase the specificity and effectiveness of antiandrogen treatment for men with castrate resistant prostate cancer. The ability to deliver higher drug concentrations in prostate cancer cells may translate into improved clinical end points including overall survival.


Assuntos
Antagonistas de Androgênios/química , Antagonistas de Androgênios/farmacologia , Nanopartículas/química , Antígeno Prostático Específico/metabolismo , Receptores Androgênicos/metabolismo , Antígenos de Superfície/metabolismo , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Humanos , Células MCF-7 , Masculino , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/metabolismo
15.
Proc Natl Acad Sci U S A ; 112(10): E1106-15, 2015 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-25713380

RESUMO

Two decades after the discovery of the first animal microRNA (miRNA), the number of miRNAs in animal genomes remains a vexing question. Here, we report findings from analyzing 1,323 short RNA sequencing samples (RNA-seq) from 13 different human tissue types. Using stringent thresholding criteria, we identified 3,707 statistically significant novel mature miRNAs at a false discovery rate of ≤ 0.05 arising from 3,494 novel precursors; 91.5% of these novel miRNAs were identified independently in 10 or more of the processed samples. Analysis of these novel miRNAs revealed tissue-specific dependencies and a commensurate low Jaccard similarity index in intertissue comparisons. Of these novel miRNAs, 1,657 (45%) were identified in 43 datasets that were generated by cross-linking followed by Argonaute immunoprecipitation and sequencing (Ago CLIP-seq) and represented 3 of the 13 tissues, indicating that these miRNAs are active in the RNA interference pathway. Moreover, experimental investigation through stem-loop PCR of a random collection of newly discovered miRNAs in 12 cell lines representing 5 tissues confirmed their presence and tissue dependence. Among the newly identified miRNAs are many novel miRNA clusters, new members of known miRNA clusters, previously unreported products from uncharacterized arms of miRNA precursors, and previously unrecognized paralogues of functionally important miRNA families (e.g., miR-15/107). Examination of the sequence conservation across vertebrate and invertebrate organisms showed 56.7% of the newly discovered miRNAs to be human-specific whereas the majority (94.4%) are primate lineage-specific. Our findings suggest that the repertoire of human miRNAs is far more extensive than currently represented by public repositories and that there is a significant number of lineage- and/or tissue-specific miRNAs that are uncharacterized.


Assuntos
MicroRNAs/genética , Primatas/genética , Animais , Sequência de Bases , Técnicas de Silenciamento de Genes , Genoma , Ribonuclease III/genética , Alinhamento de Sequência
16.
Curr Treat Options Oncol ; 18(6): 37, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28540598

RESUMO

OPINION STATEMENT: The genomic landscape of metastatic prostate cancer (mPCa) reveals that up to 90% of patients harbor actionable mutations and >20% have somatic DNA repair gene defects (DRD). This provides the therapeutic rationale of PARP inhibition (PARPi) to achieve "synthetic lethality" in treating this fatal disease. Clinical trials with PARP inhibitors have shown significant response rates up to 88% for PCa patients having DRD like BRCA1/2 or ATM mutations. The FDA has awarded "breakthrough designation" to develop the PARPi olaparib in treating this subset of metastatic PCa patients. The search for predictive biomarkers has expanded the realm of DNA repair genetic defects and combination genetic platforms are being evaluated as tools to assess potential "BRCAness" of tumors. Ongoing clinical trials seek to determine the optimal timing and sequence of using these agents in current PCa treatment algorithms. Combination strategies of PARPi with chemo-, radiation, and hormonal therapies, targeted agents, and immunotherapy are promising avenues of current research. Multi-center international collaborations in well-designed biomarker-driven clinical trials will be key to harness the potential of PARPi in managing a heterogeneous disease like prostate cancer.


Assuntos
Antineoplásicos/uso terapêutico , Terapia de Alvo Molecular , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Neoplasias da Próstata/tratamento farmacológico , Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais , Ensaios Clínicos como Assunto , Terapia Combinada , Reparo do DNA , Gerenciamento Clínico , Resistencia a Medicamentos Antineoplásicos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Mutação , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Medicina de Precisão/métodos , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/mortalidade , Ligação Proteica , Transcrição Gênica , Resultado do Tratamento
17.
Cancer Metastasis Rev ; 33(2-3): 399-411, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24425228

RESUMO

Prostate cancer (PCa) remains a leading cause of cancer-related death in the USA. While localized lesions are effectively treated through radical prostatectomy and/or radiation therapy, treatment for metastatic disease leverages the addiction of these tumors on the androgen receptor (AR) signaling axis for growth and disease progression. Though initially effective, tumors resistant to AR-directed therapeutics ultimately arise (a stage of the disease known as castration-resistant prostate cancer) and are responsible for PCa-specific mortality. Importantly, an abundance of clinical and preclinical evidence strongly implicates AR signaling cascades in the development of metastatic disease in both early and late stages, and thus a concerted effort has been made to delineate the AR-specific programs that facilitate progression to metastatic PCa. A multitude of downstream AR targets as well as critical AR cofactors have been identified which impinge upon both the AR pathway as well as associated metastatic phenotypes. This review will highlight the functional significance of these pathways to disseminated disease and define the molecular underpinnings behind these unique, AR-driven, metastatic signatures.


Assuntos
Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Receptores Androgênicos/metabolismo , Animais , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Progressão da Doença , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Metástase Neoplásica , Neoplasias da Próstata/etiologia , Neoplasias da Próstata/terapia , Receptores Androgênicos/genética , Transdução de Sinais
18.
EMBO J ; 30(19): 3885-94, 2011 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-21934649

RESUMO

FOXA transcription factors are potent, context-specific mediators of development that hold specialized functions in hormone-dependent tissues. Over the last several years, FOXA1 has emerged as a critical mediator of nuclear steroid receptor signalling, manifest at least in part through regulation of androgen receptor and oestrogen receptor activity. Recent findings point towards a major role for FOXA1 in modulating nuclear steroid receptor activity in breast and prostate cancer, and suggest that FOXA1 may significantly contribute to pro-tumourigenic phenotypes. The present review article will focus on the mechanisms, consequence, and clinical relevance of FOXA1-mediated steroid nuclear receptor signalling in human malignancy.


Assuntos
Regulação Neoplásica da Expressão Gênica , Fator 3-alfa Nuclear de Hepatócito/metabolismo , Neoplasias/metabolismo , Receptores de Esteroides/metabolismo , Animais , Neoplasias da Mama/metabolismo , Diferenciação Celular , Receptor alfa de Estrogênio/metabolismo , Feminino , Humanos , Masculino , Neoplasias da Próstata/metabolismo , Receptores Androgênicos/metabolismo , Transdução de Sinais , Transcrição Gênica
19.
Am J Pathol ; 184(10): 2608-10, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25128905

RESUMO

This commentary highlights the article by Yu et al, describing a set of novel fusion transcripts strongly associated with prostate cancer prognosis.


Assuntos
Fusão Gênica , Neoplasias da Próstata/genética , RNA Mensageiro/genética , Transcriptoma , Humanos , Masculino
20.
J Biol Chem ; 288(33): 24234-46, 2013 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-23760504

RESUMO

Pluripotent embryonic stem cells (ESCs) undergo self-renewal until stimulated to differentiate along specific lineage pathways. Many of the transcriptional networks that drive reprogramming of a self-renewing ESC to a differentiating cell have been identified. However, fundamental questions remain unanswered about the epigenetic programs that control these changes in gene expression. Here we report that the histone ubiquitin hydrolase ubiquitin-specific protease 22 (USP22) is a critical epigenetic modifier that controls this transition from self-renewal to differentiation. USP22 is induced as ESCs differentiate and is necessary for differentiation into all three germ layers. We further report that USP22 is a transcriptional repressor of the locus encoding the core pluripotency factor sex-determining region Y-box 2 (SOX2) in ESCs, and this repression is required for efficient differentiation. USP22 occupies the Sox2 promoter and hydrolyzes monoubiquitin from ubiquitylated histone H2B and blocks transcription of the Sox2 locus. Our study reveals an epigenetic mechanism that represses the core pluripotency transcriptional network in ESCs, allowing ESCs to transition from a state of self-renewal into lineage-specific differentiation programs.


Assuntos
Diferenciação Celular/genética , Células-Tronco Embrionárias/citologia , Células-Tronco Embrionárias/metabolismo , Endopeptidases/metabolismo , Epigênese Genética , Fatores de Transcrição SOXB1/genética , Transcrição Gênica , Proteases Específicas de Ubiquitina/metabolismo , Animais , Linhagem Celular , Proliferação de Células , Endopeptidases/genética , Perfilação da Expressão Gênica , Regulação da Expressão Gênica no Desenvolvimento , Loci Gênicos/genética , Histonas/metabolismo , Camundongos , Fenótipo , Células-Tronco Pluripotentes/metabolismo , Ligação Proteica/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Fatores de Transcrição SOXB1/metabolismo , Sirtuína 1/metabolismo , Ubiquitina Tiolesterase , Proteases Específicas de Ubiquitina/genética , Ubiquitinação/genética
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