RESUMO
Prostate cancer is one of the most heritable cancers. Hundreds of germline polymorphisms have been linked to prostate cancer diagnosis and prognosis. Polygenic risk scores can predict genetic risk of a prostate cancer diagnosis. Although these scores inform the probability of developing a tumor, it remains unknown how germline risk influences the tumor molecular evolution. We cultivated a cohort of 1250 localized European-descent patients with germline and somatic DNA profiling. Men of European descent with higher genetic risk were diagnosed earlier and had less genomic instability and fewer driver genes mutated. Higher genetic risk was associated with better outcome. These data imply a polygenic "two-hit" model where germline risk reduces the number of somatic alterations required for tumorigenesis. These findings support further clinical studies of polygenic risk scores as inexpensive and minimally invasive adjuncts to standard risk stratification. Further studies are required to interrogate generalizability to more ancestrally and clinically diverse populations.
Assuntos
Neoplasias da Próstata , Masculino , Humanos , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Fatores de Risco , Prognóstico , Predisposição Genética para DoençaRESUMO
PURPOSE: Chromosomal instability (CIN) is a common phenomenon in colorectal cancer, but its role and underlying cause remain unknown. We have identified that mitotic regulator microtubule-associated protein 9 (MAP9) is a critical regulator of CIN in colorectal cancer. We thus studied the effect of MAP9 loss on colorectal cancer in Map9-knockout mice and in cell lines. EXPERIMENTAL DESIGN: We generated colon epithelial-specific Map9-knockout mice and evaluated colorectal cancer development. Effect of Map9 knockout on colorectal cancer progression was determined in chemical or ApcMin /+ -induced colorectal cancer. Molecular mechanism of MAP9 was determined using spectral karyotyping, microtubule assays, and whole-genome sequencing (WGS). Clinical significance of MAP9 was examined in 141 patients with CRC. RESULTS: Spontaneous colonic tumors (9.1%) were developed in colon epithelium-specific Map9-knockout mice at 17 months, but none was observed in wild-type littermates. Map9 deletion accelerated colorectal cancer formation both in ApcMin /+ mice and azoxymethane-treated mice, and reduced survival in ApcMin /+ mice. Mechanistically, MAP9 stabilized microtubules and mediated mitotic spindle assembly. MAP9 also maintained the spindle pole integrity and protected K-fiber from depolymerization at spindle poles. MAP9 loss induced severe mitosis failure, chromosome segregation errors, and aneuploidy, leading to transformation of normal colon epithelial cells. WGS confirmed enhanced CIN in intestinal tumors from Map9 knockout ApcMin /+ mice. In patients with colorectal cancer, MAP9 was frequently silenced and its downregulation was associated with poor survival. CONCLUSIONS: MAP9 is a microtubule stabilizer that contributes to spindle stability and inhibits colorectal tumorigenesis, supporting the role of MAP9 as a tumor suppressor for preventing CIN in colorectal cancer.
Assuntos
Carcinogênese/patologia , Instabilidade Cromossômica , Neoplasias Colorretais/mortalidade , Proteínas Associadas aos Microtúbulos/metabolismo , Mitose , Aneuploidia , Animais , Apoptose , Azoximetano/toxicidade , Carcinogênese/induzido quimicamente , Carcinogênese/genética , Carcinógenos/toxicidade , Proliferação de Células , Neoplasias Colorretais/induzido quimicamente , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Humanos , Camundongos , Camundongos Knockout , Proteínas Associadas aos Microtúbulos/genética , Prognóstico , Taxa de Sobrevida , Células Tumorais CultivadasRESUMO
Oncogenesis is driven by germline, environmental and stochastic factors. It is unknown how these interact to produce the molecular phenotypes of tumors. We therefore quantified the influence of germline polymorphisms on the somatic epigenome of 589 localized prostate tumors. Predisposition risk loci influence a tumor's epigenome, uncovering a mechanism for cancer susceptibility. We identified and validated 1,178 loci associated with altered methylation in tumoral but not nonmalignant tissue. These tumor methylation quantitative trait loci influence chromatin structure, as well as RNA and protein abundance. One prominent tumor methylation quantitative trait locus is associated with AKT1 expression and is predictive of relapse after definitive local therapy in both discovery and validation cohorts. These data reveal intricate crosstalk between the germ line and the epigenome of primary tumors, which may help identify germline biomarkers of aggressive disease to aid patient triage and optimize the use of more invasive or expensive diagnostic assays.
Assuntos
Metilação de DNA/genética , Epigenoma/genética , Mutação em Linhagem Germinativa/genética , Neoplasias da Próstata/genética , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Predisposição Genética para Doença , Genoma Humano/genética , Humanos , Masculino , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Neoplasias da Próstata/patologia , Proteínas Proto-Oncogênicas c-akt/genética , Locos de Características Quantitativas/genéticaRESUMO
The transcriptome of prostate cancer is highly heterogeneous, with noncoding transcripts being essential players. Long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs) are two unique classes of noncoding RNA drawing increasing attention. Biologically, they have intriguing properties with important regulatory functions. Clinically, they present as promising biomarkers and therapeutic targets. Recent advancements in technologies have opened up new directions for noncoding RNA research, which include RNA-protein interaction, RNA secondary structure, and spatial transcriptomics. Furthermore, recent work has also evaluated the clinical applications of these noncoding RNAs in noninvasive liquid biopsy and RNA-based therapies. In this review, we summarize recent findings on lncRNAs and circRNAs in prostate cancer, discuss their clinical utilities, and highlight these exciting areas of research.
Assuntos
Biomarcadores Tumorais , Predisposição Genética para Doença , Neoplasias da Próstata/genética , RNA Longo não Codificante/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Neoplasias da Próstata/metabolismo , RNA Circular/genética , RNA Longo não Codificante/química , Proteínas de Ligação a RNA/metabolismo , Relação Estrutura-AtividadeRESUMO
PURPOSE: Protein kinases are known to play a prominent role in oncogenic progression across multiple cancer subtypes, yet their role in prostate cancer progression remains underexplored. The purpose of this study was to identify kinases that drive prostate cancer progression.Experimental Design: To discover kinases that drive prostate cancer progression, we investigated the association between gene expression of all known kinases and long-term clinical outcomes in tumor samples from 545 patients with high-risk disease. We evaluated the impact of genetic and pharmacologic inhibition of the most significant kinase associated with metastatic progression in vitro and in vivo. RESULTS: DNA-dependent protein kinase (DNAPK) was identified as the most significant kinase associated with metastatic progression in high-risk prostate cancer. Inhibition of DNAPK suppressed the growth of both AR-dependent and AR-independent prostate cancer cells. Gene set enrichment analysis nominated Wnt as the top pathway associated with DNAPK. We found that DNAPK interacts with the Wnt transcription factor LEF1 and is critical for LEF1-mediated transcription. CONCLUSIONS: Our data show that DNAPK drives prostate cancer progression through transcriptional regulation of Wnt signaling and is an attractive therapeutic target in aggressive prostate cancer.
Assuntos
Proteína Quinase Ativada por DNA/metabolismo , Regulação Neoplásica da Expressão Gênica , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Transcrição Gênica , Via de Sinalização Wnt , Animais , Biomarcadores Tumorais , Linhagem Celular Tumoral , Movimento Celular , Proteína Quinase Ativada por DNA/antagonistas & inibidores , Proteína Quinase Ativada por DNA/genética , Modelos Animais de Doenças , Progressão da Doença , Perfilação da Expressão Gênica , Técnicas de Silenciamento de Genes , Xenoenxertos , Humanos , Masculino , Camundongos , Metástase Neoplásica , Fenótipo , Neoplasias da Próstata/patologia , Neoplasias da Próstata/terapia , Ligação Proteica , RNA Interferente Pequeno/genéticaRESUMO
Neuroendocrine prostate cancer (NEPC) is a lethal subtype of prostate cancer arising mostly from adenocarcinoma via neuroendocrine transdifferentiation following androgen deprivation therapy. Mechanisms contributing to both NEPC development and its aggressiveness remain elusive. In light of the fact that hyperchromatic nuclei are a distinguishing histopathologic feature of NEPC, we utilized transcriptomic analyses of our patient-derived xenograft (PDX) models, multiple clinical cohorts, and genetically engineered mouse models to identify 36 heterochromatin-related genes that are significantly enriched in NEPC. Longitudinal analysis using our unique, first-in-field PDX model of adenocarcinoma-to-NEPC transdifferentiation revealed that, among those 36 heterochromatin-related genes, heterochromatin protein 1α (HP1α) expression increased early and steadily during NEPC development and remained elevated in the developed NEPC tumor. Its elevated expression was further confirmed in multiple PDX and clinical NEPC samples. HP1α knockdown in the NCI-H660 NEPC cell line inhibited proliferation, ablated colony formation, and induced apoptotic cell death, ultimately leading to tumor growth arrest. Its ectopic expression significantly promoted NE transdifferentiation in adenocarcinoma cells subjected to androgen deprivation treatment. Mechanistically, HP1α reduced expression of androgen receptor and RE1 silencing transcription factor and enriched the repressive trimethylated histone H3 at Lys9 mark on their respective gene promoters. These observations indicate a novel mechanism underlying NEPC development mediated by abnormally expressed heterochromatin genes, with HP1α as an early functional mediator and a potential therapeutic target for NEPC prevention and management.Significance: Heterochromatin proteins play a fundamental role in NEPC, illuminating new therapeutic targets for this aggressive disease. Cancer Res; 78(10); 2691-704. ©2018 AACR.
Assuntos
Carcinoma Neuroendócrino/patologia , Transdiferenciação Celular/genética , Proteínas Cromossômicas não Histona/genética , Proteínas Cromossômicas não Histona/metabolismo , Neoplasias da Próstata/patologia , Adenocarcinoma/patologia , Animais , Apoptose/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Sobrevivência Celular/genética , Homólogo 5 da Proteína Cromobox , Progressão da Doença , Regulação Neoplásica da Expressão Gênica/genética , Células HEK293 , Histonas/metabolismo , Humanos , Masculino , Camundongos , Transplante de Neoplasias , Interferência de RNA , Receptores Androgênicos/biossíntese , Proteínas Repressoras/biossíntese , Transplante HeterólogoRESUMO
Androgen receptor (AR) signaling is a key driver of prostate cancer, and androgen-deprivation therapy (ADT) is a standard treatment for patients with advanced and metastatic disease. However, patients receiving ADT eventually develop incurable castration-resistant prostate cancer (CRPC). Here, we report that the chromatin modifier LSD1, an important regulator of AR transcriptional activity, undergoes epigenetic reprogramming in CRPC. LSD1 reprogramming in this setting activated a subset of cell-cycle genes, including CENPE, a centromere binding protein and mitotic kinesin. CENPE was regulated by the co-binding of LSD1 and AR to its promoter, which was associated with loss of RB1 in CRPC. Notably, genetic deletion or pharmacological inhibition of CENPE significantly decreases tumor growth. Our findings show how LSD1-mediated epigenetic reprogramming drives CRPC, and they offer a mechanistic rationale for its therapeutic targeting in this disease. Cancer Res; 77(20); 5479-90. ©2017 AACR.
Assuntos
Proteínas Cromossômicas não Histona/metabolismo , Histona Desmetilases/genética , Neoplasias de Próstata Resistentes à Castração/enzimologia , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias da Próstata/embriologia , Neoplasias da Próstata/genética , Androgênios/metabolismo , Animais , Linhagem Celular Tumoral , Reprogramação Celular/genética , Proteínas Cromossômicas não Histona/biossíntese , Proteínas Cromossômicas não Histona/genética , Progressão da Doença , Epigênese Genética , Xenoenxertos , Histona Desmetilases/metabolismo , Humanos , Masculino , Camundongos , Neoplasias da Próstata/metabolismo , Neoplasias de Próstata Resistentes à Castração/metabolismo , Transdução de Sinais , TransfecçãoRESUMO
UNLABELLED: Overexpression of EZH2 is frequently linked to the advanced and metastatic stage of cancers. The mechanisms of its oncogenic function can be context specific, and may vary depending on the protein complexes that EZH2 interacts with. To identify novel transcriptional collaborators of EZH2 in cancers, a computational approach was developed that integrates protein-DNA binding data, cell perturbation gene expression data, and compendiums of tumor expression profiles. This holistic approach identified E2F1, a known mediator of the Rb tumor suppressor, as a transcriptional collaborator of EZH2 in castration-resistant prostate cancer. Subsequent analysis and experimental validation found EZH2 and E2F1 cobind to a subset of chromatin sites lacking H3K27 trimethylation, and activate genes that are critical for prostate cancer progression. The collaboration of EZH2 and E2F1 in transcriptional regulation is also observed in diffuse large B-cell lymphoma cell lines, where activation of the transcriptional network is concordant with the cellular response to the EZH2 inhibitor. IMPLICATIONS: The direct collaboration between EZH2 and Rb/E2F1 pathway provides an innovative mechanism underlying the cascade of tumor progression, and lays the foundation for the development of new anticancer targets/strategies.
Assuntos
Biologia Computacional/métodos , Fator de Transcrição E2F1/metabolismo , Linfoma Difuso de Grandes Células B/genética , Complexo Repressor Polycomb 2/metabolismo , Neoplasias de Próstata Resistentes à Castração/genética , Transcrição Gênica , Linhagem Celular Tumoral , Cromatina/metabolismo , Progressão da Doença , Fator de Transcrição E2F1/genética , Proteína Potenciadora do Homólogo 2 de Zeste , Epigênese Genética , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Linfoma Difuso de Grandes Células B/metabolismo , Masculino , Complexo Repressor Polycomb 2/genética , Neoplasias de Próstata Resistentes à Castração/metabolismo , Ligação ProteicaRESUMO
UNLABELLED: Transcription factor binding events are frequently associated with a pattern of nucleosome occupancy changes in which nucleosomes flanking the binding site increase in occupancy, while those in the vicinity of the binding site itself are displaced. Genome-wide information on enhancer proximal nucleosome occupancy can be readily acquired using ChIP-seq targeting enhancer-related histone modifications such as H3K4me2. Here, we present a software package, BINOCh that allows biologists to use such data to infer the identity of key transcription factors that regulate the response of a cell to a stimulus or determine a program of differentiation. AVAILABILITY: The BINOCh open source Python package is freely available at http://liulab.dfci.harvard.edu/BINOCh under the FreeBSD license.