RESUMO
The preferentially expressed antigen in melanoma (PRAME) is expressed in several hematologic malignancies, but either is not expressed or is expressed at only low levels in normal hematopoietic cells, making it a target for cancer therapy. PRAME is a tumor-associated antigen and has been described as a corepressor of retinoic acid signaling in solid tumor cells, but its function in hematopoietic cells is unknown. PRAME mRNA expression increased with chronic myeloid leukemia (CML) disease progression and its detection in late chronic-phase CML patients before tyrosine kinase inhibitor therapy was associated with poorer therapeutic responses and ABL tyrosine kinase domain point mutations. In leukemia cell lines, PRAME protein expression inhibited granulocytic differentiation only in cell lines that differentiate along this lineage after all-trans retinoic acid (ATRA) exposure. Forced PRAME expression in normal hematopoietic progenitors, however, inhibited myeloid differentiation both in the presence and absence of ATRA, and this phenotype was reversed when PRAME was silenced in primary CML progenitors. These observations suggest that PRAME inhibits myeloid differentiation in certain myeloid leukemias, and that its function in these cells is lineage and phenotype dependent. Lastly, these observations suggest that PRAME is a target for both prognostic and therapeutic applications.
Assuntos
Antígenos de Neoplasias/biossíntese , Diferenciação Celular , Regulação Leucêmica da Expressão Gênica , Granulócitos/metabolismo , Células-Tronco Hematopoéticas/metabolismo , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Células-Tronco Neoplásicas/metabolismo , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Progressão da Doença , Feminino , Inativação Gênica , Granulócitos/patologia , Células-Tronco Hematopoéticas/patologia , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Masculino , Células-Tronco Neoplásicas/patologia , Prognóstico , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-abl/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-abl/metabolismo , Tretinoína/farmacologiaRESUMO
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
RESUMO
Histone deacetylase inhibitors comprise a variety of natural and synthetic compounds, which have in common that they inhibit enzymes that mediate the removal of acetyl groups from a range of proteins, including nucleosomal histones. Histone deacetylase inhibitors have anti-cancer activities in vitro and in vivo and are used in the clinic for the treatment of advanced cutaneous T cell lymphoma. The molecular pathways targeted by these compounds are discussed with an emphasis on the effects of these compounds on retinoic acid signaling.
Assuntos
Antineoplásicos/farmacologia , Inibidores Enzimáticos/farmacologia , Inibidores de Histona Desacetilases , Histonas/metabolismo , Neoplasias/tratamento farmacológico , Animais , Antineoplásicos/uso terapêutico , Metilação de DNA , Epigênese Genética , Histona Desacetilases/metabolismo , Humanos , Linfoma Cutâneo de Células T/tratamento farmacológico , Modelos Biológicos , Neoplasias/enzimologia , Neoplasias/metabolismo , Tretinoína/metabolismoRESUMO
Tumor antigens are of interest as diagnostic and prognostic markers and potential therapeutic targets. The tumor antigen preferentially expressed antigen of melanoma (PRAME) is frequently overexpressed in a wide variety of cancers and is a prognostic marker for clinical outcome. It has been shown recently that PRAME functions as a repressor of retinoic acid signaling. Here, we discuss this novel insight in the context of the increasing interest in tumor antigens as targets for therapy.
Assuntos
Antígenos de Neoplasias/fisiologia , Neoplasias/imunologia , Antígenos de Neoplasias/biossíntese , Biomarcadores Tumorais/biossíntese , HumanosRESUMO
UNLABELLED: Prostate cancer is the most prevalent cancer in males, and treatment options are limited for advanced forms of the disease. Loss of the PTEN and TP53 tumor suppressor genes is commonly observed in prostate cancer, whereas their compound loss is often observed in advanced prostate cancer. Here, we show that PARP inhibition triggers a p53-dependent cellular senescence in a PTEN-deficient setting in the prostate. Surprisingly, we also find that PARP-induced cellular senescence is morphed into an apoptotic response upon compound loss of PTEN and p53. We further show that superactivation of the prosurvival PI3K-AKT signaling pathway limits the efficacy of a PARP single-agent treatment, and that PARP and PI3K inhibitors effectively synergize to suppress tumorigenesis in human prostate cancer cell lines and in a Pten/Trp53-deficient mouse model of advanced prostate cancer. Our findings, therefore, identify a combinatorial treatment with PARP and PI3K inhibitors as an effective option for PTEN-deficient prostate cancer. SIGNIFICANCE: The paucity of therapeutic options in advanced prostate cancer displays an urgent need for the preclinical assessment of novel therapeutic strategies. We identified differential therapeutic vulnerabilities that emerge upon the loss of both PTEN and p53, and observed that combined inhibition of PARP and PI3K provides increased efficacy in hormone-insensitive advanced prostate cancer.
Assuntos
Elafina/genética , PTEN Fosfo-Hidrolase/genética , Poli(ADP-Ribose) Polimerases/genética , Neoplasias da Próstata/tratamento farmacológico , Proteína Supressora de Tumor p53/genética , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Senescência Celular/efeitos dos fármacos , Elafina/antagonistas & inibidores , Humanos , Masculino , Camundongos , Terapia de Alvo Molecular , Inibidores de Poli(ADP-Ribose) Polimerases , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologiaRESUMO
Here we report an integrated analysis that leverages data from treatment of genetic mouse models of prostate cancer along with clinical data from patients to elucidate new mechanisms of castration resistance. We show that castration counteracts tumor progression in a Pten loss-driven mouse model of prostate cancer through the induction of apoptosis and proliferation block. Conversely, this response is bypassed with deletion of either Trp53 or Zbtb7a together with Pten, leading to the development of castration-resistant prostate cancer (CRPC). Mechanistically, the integrated acquisition of data from mouse models and patients identifies the expression patterns of XAF1, XIAP and SRD5A1 as a predictive and actionable signature for CRPC. Notably, we show that combined inhibition of XIAP, SRD5A1 and AR pathways overcomes castration resistance. Thus, our co-clinical approach facilitates the stratification of patients and the development of tailored and innovative therapeutic treatments.
Assuntos
Antagonistas de Androgênios/uso terapêutico , Androgênios/metabolismo , Neoplasias da Próstata/terapia , Terapias em Estudo , Animais , Antineoplásicos/uso terapêutico , Benzamidas , Linhagem Celular Tumoral , Avaliação Pré-Clínica de Medicamentos , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Modelos Biológicos , Nitrilas , Orquiectomia , PTEN Fosfo-Hidrolase/genética , Feniltioidantoína/análogos & derivados , Feniltioidantoína/uso terapêutico , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Pesquisa Translacional Biomédica/métodos , Falha de TratamentoRESUMO
The retinoid X receptor (RXR)-agonist bexarotene and the histone deacetylase inhibitor (HDACI) vorinostat are each established monotherapies for cutaneous T-cell lymphomas (CTCLs). We investigated the combination of HDACI and retinoic acid receptor (RAR)/RXR agonists in vitro and in a phase I, multicenter, open-label, two-part dose-escalation study. The combination of bexarotene with a HDACI in vitro leads to cooperative activation of gene transcription and reduction of cell viability in human tumor cell lines. The primary clinical objective was to determine the maximum tolerated dose (MTD) of bexarotene plus vorinostat in 23 patients with CTCLs. The MTD for part I was established at vorinostat 200 mg/day plus bexarotene 300 mg/m(2)/day. The MTD for part II was not reached. Four patients had an objective response and seven patients experienced pruritus relief. We conclude that concomitant administration of vorinostat and bexarotene is feasible only if lower doses of each drug are administered relative to the product label monotherapy doses.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Inibidores de Histona Desacetilases/farmacologia , Ácidos Hidroxâmicos/administração & dosagem , Linfoma Cutâneo de Células T/tratamento farmacológico , Receptores do Ácido Retinoico/metabolismo , Receptores X de Retinoides/metabolismo , Tetra-Hidronaftalenos/administração & dosagem , Adulto , Idoso , Bexaroteno , Linhagem Celular Tumoral , Sobrevivência Celular , Feminino , Humanos , Técnicas In Vitro , Masculino , Pessoa de Meia-Idade , Transcrição Gênica , VorinostatRESUMO
We have previously reported a gene expression signature that is a powerful predictor of poor clinical outcome in breast cancer. Among the seventy genes in this expression profile is a gene of unknown function: TSPYL5 (TSPY-like 5, also known as KIAA1750). TSPYL5 is located within a small region at chromosome 8q22 that is frequently amplified in breast cancer, which suggests that TSPYL5 has a causal role in breast oncogenesis. Here, we report that high TSPYL5 expression is an independent marker of poor outcome in breast cancer. Mass spectrometric analysis revealed that TSPYL5 interacts with ubiquitin-specific protease 7 (USP7; also known as herpesvirus-associated ubiquitin-specific protease; HAUSP). USP7 is the deubiquitylase for the p53 tumour suppressor and TSPYL5 reduces the activity of USP7 towards p53, resulting in increased p53 ubiquitylation. We demonstrate that TSPYL5 reduces p53 protein levels and inhibits activation of p53-target genes. Furthermore, expression of TSPYL5 overrides p53-dependent proliferation arrest and oncogene-induced senescence, and contributes to oncogenic transformation in multiple cell-based assays. Our data identify TSPYL5 as a suppressor of p53 function through its interaction with USP7.
Assuntos
Neoplasias da Mama/genética , Proteínas Nucleares/genética , Proteína Supressora de Tumor p53/genética , Ubiquitina Tiolesterase/genética , Sequência de Aminoácidos , Animais , Western Blotting , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular , Linhagem Celular Tumoral , Cromossomos Humanos Par 8/genética , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Imunoprecipitação , Estimativa de Kaplan-Meier , Espectrometria de Massas , Dados de Sequência Molecular , Proteínas Nucleares/metabolismo , Prognóstico , Ligação Proteica , Interferência de RNA , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Proteína Supressora de Tumor p53/metabolismo , Ubiquitina Tiolesterase/metabolismo , Peptidase 7 Específica de Ubiquitina , UbiquitinaçãoRESUMO
To identify potential biomarkers of therapy response, we have previously done a large-scale gain-of-function genetic screen to identify genes whose expression confers resistance to histone deacetylase inhibitors (HDACI). This genetic screen identified two genes with a role in retinoic acid signaling, suggesting that HDACIs target retinoic acid signaling as part of their anticancer effect. We study here a third gene identified in this genetic screen, UNC45A, and assess its role in retinoic acid signaling and responses to HDACIs using cell-based proliferation and differentiation assays and transcriptional reporter gene assays. The vertebrate Unc45 genes are known for their roles in muscle development and the assembly and cochaperoning of the muscle motor protein myosin. Here, we report that human UNC45A (GCUNC45) can render transformed cells resistant to treatment with HDACIs. We show that UNC45A also inhibits signaling through the retinoic acid receptor alpha. Expression of UNC45A inhibits retinoic acid-induced proliferation arrest and differentiation of human neuroblastoma cells and inhibits the induction of endogenous retinoic acid receptor target genes. These data establish an unexpected role for UNC45A in causing resistance to both HDACI drugs and retinoic acid. Moreover, our data lend further support to the notion that HDACIs exert their anticancer effect, at least in part, through an effect on retinoic acid signaling.
Assuntos
Inibidores de Histona Desacetilases/farmacologia , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Tretinoína/farmacologia , Sequência de Aminoácidos , Animais , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/genética , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/patologia , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/fisiologia , Processos de Crescimento Celular/efeitos dos fármacos , Processos de Crescimento Celular/fisiologia , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Histona Desacetilases/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Camundongos , Dados de Sequência Molecular , Neuroblastoma/tratamento farmacológico , Neuroblastoma/genética , Neuroblastoma/metabolismo , Neuroblastoma/patologia , Osteossarcoma/tratamento farmacológico , Osteossarcoma/genética , Osteossarcoma/metabolismo , Osteossarcoma/patologia , Receptores do Ácido Retinoico/genética , Receptores do Ácido Retinoico/metabolismo , Receptor alfa de Ácido Retinoico , Transdução de Sinais/efeitos dos fármacos , Tretinoína/antagonistas & inibidores , Tretinoína/metabolismoRESUMO
Aberrant acetylation has been strongly linked to tumorigenesis, and the modulation of acetylation through targeting histone deacetylases (HDACs) is gathering increasing pace as a viable therapeutic strategy. A genome-wide loss-of-function screen identified HR23B, which shuttles ubiquitinated cargo proteins to the proteasome, as a sensitivity determinant for HDAC inhibitor-induced apoptosis. HR23B also governs tumor cell sensitivity to drugs that act directly on the proteasome. The level of HR23B influences the response of tumor cells to HDAC inhibitors, and HR23B is found at high levels in cutaneous T cell lymphoma in situ, a malignancy that responds favorably to HDAC inhibitor-based therapy. These results suggest that deregulated proteasome activity contributes to the anticancer activity of HDAC inhibitors.
Assuntos
Apoptose/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Genoma/genética , Inibidores de Histona Desacetilases , Complexo de Endopeptidases do Proteassoma/metabolismo , Animais , Biópsia , Linhagem Celular Tumoral , Proteínas de Ligação a DNA/deficiência , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Avaliação Pré-Clínica de Medicamentos , Regulação Neoplásica da Expressão Gênica , Histona Desacetilases/metabolismo , Linfoma Cutâneo de Células T/metabolismo , Camundongos , Camundongos Knockout , Interferência de RNA , Neoplasias Cutâneas/metabolismo , Especificidade por SubstratoRESUMO
Retinoids play key roles in differentiation, growth arrest, and apoptosis and are increasingly being used in the clinic for the treatment of a variety of cancers, including neuroblastoma. Here, using a large-scale RNA interference-based genetic screen, we identify ZNF423 (also known as Ebfaz, OAZ, or Zfp423) as a component critically required for retinoic acid (RA)-induced differentiation. ZNF423 associates with the RARalpha/RXRalpha nuclear receptor complex and is essential for transactivation in response to retinoids. Downregulation of ZNF423 expression by RNA interference in neuroblastoma cells results in a growth advantage and resistance to RA-induced differentiation, whereas overexpression of ZNF423 leads to growth inhibition and enhanced differentiation. Finally, we show that low ZNF423 expression is associated with poor disease outcome in neuroblastoma patients.
Assuntos
Antineoplásicos/farmacologia , Diferenciação Celular , Proteínas de Ligação a DNA/metabolismo , Neuroblastoma/metabolismo , Neuroblastoma/patologia , Tretinoína/farmacologia , Adolescente , Criança , Pré-Escolar , Imunoprecipitação da Cromatina , Proteínas de Ligação a DNA/genética , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Prognóstico , Regiões Promotoras Genéticas , Proteínas , Receptores do Ácido Retinoico/genética , Receptores do Ácido Retinoico/metabolismo , Receptor alfa de Ácido Retinoico , Taxa de Sobrevida , Teratocarcinoma/metabolismo , Teratocarcinoma/patologia , Dedos de ZincoRESUMO
Understanding the pathways that are targeted by cancer drugs is instrumental for their rational use in a clinical setting. Inhibitors of histone deacetylases (HDACI) selectively inhibit proliferation of malignant cells and are used for the treatment of cancer, but their cancer selectivity is understood poorly. We conducted a functional genetic screen to address the mechanism(s) of action of HDACI. We report here that ectopic expression of two genes that act on retinoic acid (RA) signaling can cause resistance to growth arrest and apoptosis induced by HDACI of different chemical classes: the retinoic acid receptor alpha (RARalpha) and preferentially expressed antigen of melanoma (PRAME), a repressor of RA signaling. Treatment of cells with HDACI induced RA signaling, which was inhibited by RARalpha or PRAME expression. Conversely, RAR-deficient cells and PRAME-knockdown cells show enhanced sensitivity to HDACI in vitro and in mouse xenograft models. Finally, a combination of RA and HDACI acted synergistically to activate RA signaling and inhibit tumor growth. These experiments identify the RA pathway as a rate-limiting target of HDACI and suggest strategies to enhance the therapeutic efficacy of HDACI.
Assuntos
Testes Genéticos/métodos , Inibidores de Histona Desacetilases , Histona Desacetilases/genética , Tretinoína/fisiologia , Animais , Divisão Celular/efeitos dos fármacos , Ensaio de Unidades Formadoras de Colônias , Embrião de Mamíferos , Inibidores Enzimáticos/farmacologia , Fibroblastos/fisiologia , Humanos , Camundongos , Transplante de Neoplasias , Receptores do Ácido Retinoico/genética , Receptores do Ácido Retinoico/fisiologia , Receptor alfa de Ácido Retinoico , Transplante Heterólogo , Tretinoína/farmacologiaRESUMO
Retinoic acid (RA) induces proliferation arrest, differentiation, and apoptosis, and defects in retinoic acid receptor (RAR) signaling have been implicated in cancer. The human tumor antigen PRAME is overexpressed in a variety of cancers, but its function has remained unclear. We identify here PRAME as a dominant repressor of RAR signaling. PRAME binds to RAR in the presence of RA, preventing ligand-induced receptor activation and target gene transcription through recruitment of Polycomb proteins. PRAME is present at RAR target promoters and inhibits RA-induced differentiation, growth arrest, and apoptosis. Conversely, knockdown of PRAME expression by RNA interference in RA-resistant human melanoma restores RAR signaling and reinstates sensitivity to the antiproliferative effects of RA in vitro and in vivo. Our data suggest that overexpression of PRAME frequently observed in human cancers confers growth or survival advantages by antagonizing RAR signaling.