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1.
Am J Hum Genet ; 106(3): 405-411, 2020 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-32109420

RESUMO

Recurrent somatic variants in SPOP are cancer specific; endometrial and prostate cancers result from gain-of-function and dominant-negative effects toward BET proteins, respectively. By using clinical exome sequencing, we identified six de novo pathogenic missense variants in SPOP in seven individuals with developmental delay and/or intellectual disability, facial dysmorphisms, and congenital anomalies. Two individuals shared craniofacial dysmorphisms, including congenital microcephaly, that were strikingly different from those of the other five individuals, who had (relative) macrocephaly and hypertelorism. We measured the effect of SPOP variants on BET protein amounts in human Ishikawa endometrial cancer cells and patient-derived cell lines because we hypothesized that variants would lead to functional divergent effects on BET proteins. The de novo variants c.362G>A (p.Arg121Gln) and c. 430G>A (p.Asp144Asn), identified in the first two individuals, resulted in a gain of function, and conversely, the c.73A>G (p.Thr25Ala), c.248A>G (p.Tyr83Cys), c.395G>T (p.Gly132Val), and c.412C>T (p.Arg138Cys) variants resulted in a dominant-negative effect. Our findings suggest that these opposite functional effects caused by the variants in SPOP result in two distinct and clinically recognizable syndromic forms of intellectual disability with contrasting craniofacial dysmorphisms.


Assuntos
Mutação de Sentido Incorreto , Transtornos do Neurodesenvolvimento/genética , Proteínas Nucleares/genética , Proteínas Repressoras/genética , Adolescente , Criança , Pré-Escolar , Fácies , Feminino , Humanos , Lactente , Deficiência Intelectual/genética , Masculino , Crânio/anormalidades , Adulto Jovem
2.
Artigo em Inglês | MEDLINE | ID: mdl-39239102

RESUMO

The crosstalk between metabolism and epigenetics is an emerging field that is gaining importance in different areas such as cancer and aging, where changes in metabolism significantly impacts the cellular epigenome, in turn dictating changes in chromatin as an adaptive mechanism to bring back metabolic homeostasis. A key metabolic pathway influencing an organism's epigenetic state is one-carbon metabolism (OCM), which includes the folate and methionine cycles. Together, these cycles generate S-adenosylmethionine (SAM), the universal methyl donor essential for DNA and histone methylation. SAM serves as the sole methyl group donor for DNA and histone methyltransferases, making it a crucial metabolite for chromatin modifications. In this review, we will discuss how SAM and its byproduct, S-adenosylhomocysteine (SAH), along with the enzymes and cofactors involved in OCM, may function in the different cellular compartments, particularly in the nucleus, to directly regulate the epigenome in aging and cancer.

3.
Nat Cell Biol ; 26(6): 975-990, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38862786

RESUMO

Identifying the adaptive mechanisms of metastatic cancer cells remains an elusive question in the treatment of metastatic disease, particularly in pancreatic cancer (pancreatic adenocarcinoma, PDA). A loss-of-function shRNA targeted screen in metastatic-derived cells identified Gstt1, a member of the glutathione S-transferase superfamily, as uniquely required for dissemination and metastasis, but dispensable for primary tumour growth. Gstt1 is expressed in latent disseminated tumour cells (DTCs), is retained within a subpopulation of slow-cycling cells within existing metastases, and its inhibition leads to complete regression of macrometastatic tumours. This distinct Gstt1high population is highly metastatic and retains slow-cycling phenotypes, epithelial-mesenchymal transition features and DTC characteristics compared to the Gstt1low population. Mechanistic studies indicate that in this subset of cancer cells, Gstt1 maintains metastases by binding and glutathione-modifying intracellular fibronectin, in turn promoting its secretion and deposition into the metastatic microenvironment. We identified Gstt1 as a mediator of metastasis, highlighting the importance of heterogeneity and its influence on the metastatic tumour microenvironment.


Assuntos
Glutationa Transferase , Neoplasias Pancreáticas , Microambiente Tumoral , Glutationa Transferase/metabolismo , Glutationa Transferase/genética , Humanos , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/enzimologia , Neoplasias Pancreáticas/metabolismo , Animais , Linhagem Celular Tumoral , Transição Epitelial-Mesenquimal , Fibronectinas/metabolismo , Metástase Neoplásica , Adenocarcinoma/genética , Adenocarcinoma/patologia , Adenocarcinoma/metabolismo , Adenocarcinoma/enzimologia , Sobrevivência Celular , Regulação Neoplásica da Expressão Gênica , Camundongos , Feminino , Camundongos Endogâmicos C57BL
4.
Nat Metab ; 5(12): 2131-2147, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37957387

RESUMO

Glutamine is a critical metabolite for rapidly proliferating cells as it is used for the synthesis of key metabolites necessary for cell growth and proliferation. Glutamine metabolism has been proposed as a therapeutic target in cancer and several chemical inhibitors are in development or in clinical trials. How cells subsist when glutamine is limiting is poorly understood. Here, using an unbiased screen, we identify ALDH18A1, which encodes P5CS, the rate-limiting enzyme in the proline biosynthetic pathway, as a gene that cells can downregulate in response to glutamine starvation. Notably, P5CS downregulation promotes de novo glutamine synthesis, highlighting a previously unrecognized metabolic plasticity of cancer cells. The glutamate conserved from reducing proline synthesis allows cells to produce the key metabolites necessary for cell survival and proliferation under glutamine-restricted conditions. Our findings reveal an adaptive pathway that cancer cells acquire under nutrient stress, identifying proline biosynthesis as a previously unrecognized major consumer of glutamate, a pathway that could be exploited for developing effective metabolism-driven anticancer therapies.


Assuntos
Glutamina , Neoplasias , Humanos , Glutamina/metabolismo , Proliferação de Células , Prolina , Glutamatos
5.
Cancer Lett ; 529: 11-18, 2022 03 31.
Artigo em Inglês | MEDLINE | ID: mdl-34974131

RESUMO

Comprehensive cancer genome studies have revealed genetically-defined subtypes of prostate cancer with distinct truncal driver mutations. Because prostate cancer has been largely seen as a rather uniform disease, the clinical significance of this discovery remained largely obscure. However, recent findings imply distinct biological features and therapeutic vulnerabilities linked to specific truncal mutations. Here we review our current understanding of prostate cancers harboring recurrent point mutations in the ubiquitin ligase adaptor protein SPOP and discuss opportunities for future clinical translation. More specifically, activation of the androgen receptor (AR) signaling emerges as the key oncogenic pathway. SPOP-mutant prostate cancer patients respond to AR inhibition in various clinical settings. Molecular insights on how mutant SPOP promotes tumorigenesis may open more specific therapeutic avenues which, in combination with conventional AR-targeting agents, could improve the outcome of patients with SPOP-mutant prostate cancer.


Assuntos
Biomarcadores Tumorais , Mutação , Proteínas Nucleares/genética , Neoplasias da Próstata/etiologia , Proteínas Repressoras/genética , Alelos , Tomada de Decisão Clínica , Gerenciamento Clínico , Suscetibilidade a Doenças , Regulação Neoplásica da Expressão Gênica , Predisposição Genética para Doença , Genótipo , Humanos , Mutação com Perda de Função , Masculino , Modelos Biológicos , Modelos Moleculares , Proteínas Nucleares/química , Proteínas Nucleares/metabolismo , Assistência ao Paciente , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/terapia , Conformação Proteica , Proteínas Repressoras/química , Proteínas Repressoras/metabolismo , Transdução de Sinais , Relação Estrutura-Atividade
6.
Trends Cancer ; 7(9): 823-836, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34031014

RESUMO

Cancer is the dysregulated proliferation of cells caused by acquired mutations in key driver genes. The most frequently mutated driver genes promote tumorigenesis in various organisms, cell types, and genetic backgrounds. However, recent cancer genomics studies also point to the existence of context-dependent driver gene functions, where specific mutations occur predominately or even exclusively in certain tumor types or genetic backgrounds. Here, we review examples of co-occurring and mutually exclusive driver gene mutation patterns across cancer genomes and discuss their underlying biology. While co-occurring driver genes typically activate collaborating oncogenic pathways, we identify two distinct biological categories of incompatibilities among the mutually exclusive driver genes depending on whether the mutated drivers trigger the same or divergent tumorigenic pathways. Finally, we discuss possible therapeutic avenues emerging from the study of incompatible driver gene mutations.


Assuntos
Algoritmos , Neoplasias , Carcinogênese/genética , Genômica , Humanos , Mutação , Neoplasias/genética
7.
Nat Commun ; 12(1): 734, 2021 02 02.
Artigo em Inglês | MEDLINE | ID: mdl-33531470

RESUMO

Driver genes with a mutually exclusive mutation pattern across tumor genomes are thought to have overlapping roles in tumorigenesis. In contrast, we show here that mutually exclusive prostate cancer driver alterations involving the ERG transcription factor and the ubiquitin ligase adaptor SPOP are synthetic sick. At the molecular level, the incompatible cancer pathways are driven by opposing functions in SPOP. ERG upregulates wild type SPOP to dampen androgen receptor (AR) signaling and sustain ERG activity through degradation of the bromodomain histone reader ZMYND11. Conversely, SPOP-mutant tumors stabilize ZMYND11 to repress ERG-function and enable oncogenic androgen receptor signaling. This dichotomy regulates the response to therapeutic interventions in the AR pathway. While mutant SPOP renders tumor cells susceptible to androgen deprivation therapies, ERG promotes sensitivity to high-dose androgen therapy and pharmacological inhibition of wild type SPOP. More generally, these results define a distinct class of antagonistic cancer drivers and a blueprint toward their therapeutic exploitation.


Assuntos
Proteínas Nucleares/metabolismo , Proteínas Oncogênicas/metabolismo , Neoplasias da Próstata/metabolismo , Proteínas Repressoras/metabolismo , Regulador Transcricional ERG/metabolismo , Complexos Ubiquitina-Proteína Ligase/metabolismo , Animais , Biomarcadores Tumorais/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Proteínas Correpressoras/genética , Proteínas Correpressoras/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Células HEK293 , Humanos , Imuno-Histoquímica , Imunoprecipitação , Masculino , Camundongos , Camundongos Nus , Mutação/genética , Proteínas Nucleares/genética , Proteínas Oncogênicas/genética , Neoplasias da Próstata/genética , Ligação Proteica , Proteômica , Receptores Androgênicos/metabolismo , Proteínas Repressoras/genética , Transdução de Sinais/fisiologia , Regulador Transcricional ERG/genética , Complexos Ubiquitina-Proteína Ligase/genética
8.
Nat Med ; 23(9): 1046-1054, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28805821

RESUMO

It is generally assumed that recurrent mutations within a given cancer driver gene elicit similar drug responses. Cancer genome studies have identified recurrent but divergent missense mutations affecting the substrate-recognition domain of the ubiquitin ligase adaptor SPOP in endometrial and prostate cancers. The therapeutic implications of these mutations remain incompletely understood. Here we analyzed changes in the ubiquitin landscape induced by endometrial cancer-associated SPOP mutations and identified BRD2, BRD3 and BRD4 proteins (BETs) as SPOP-CUL3 substrates that are preferentially degraded by endometrial cancer-associated SPOP mutants. The resulting reduction of BET protein levels sensitized cancer cells to BET inhibitors. Conversely, prostate cancer-specific SPOP mutations resulted in impaired degradation of BETs, promoting their resistance to pharmacologic inhibition. These results uncover an oncogenomics paradox, whereby mutations mapping to the same domain evoke opposing drug susceptibilities. Specifically, we provide a molecular rationale for the use of BET inhibitors to treat patients with endometrial but not prostate cancer who harbor SPOP mutations.


Assuntos
Adenocarcinoma de Células Claras/genética , Carcinoma Endometrioide/genética , Carcinossarcoma/genética , Neoplasias do Endométrio/genética , Neoplasias Císticas, Mucinosas e Serosas/genética , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Neoplasias da Próstata/genética , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas de Ligação a RNA/metabolismo , Proteínas Repressoras/genética , Fatores de Transcrição/metabolismo , Acetanilidas/farmacologia , Adenocarcinoma de Células Claras/metabolismo , Animais , Apoptose/efeitos dos fármacos , Azepinas/farmacologia , Carcinoma Endometrioide/metabolismo , Carcinossarcoma/metabolismo , Proteínas de Ciclo Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cromatografia Líquida , Proteínas Culina/metabolismo , Resistencia a Medicamentos Antineoplásicos , Neoplasias do Endométrio/metabolismo , Epigênese Genética , Feminino , Compostos Heterocíclicos com 3 Anéis/farmacologia , Humanos , Immunoblotting , Imuno-Histoquímica , Imunoprecipitação , Masculino , Espectrometria de Massas , Camundongos Nus , Terapia de Alvo Molecular , Mutação , Transplante de Neoplasias , Neoplasias Císticas, Mucinosas e Serosas/metabolismo , Proteínas Nucleares/antagonistas & inibidores , Neoplasias da Próstata/metabolismo , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas de Ligação a RNA/antagonistas & inibidores , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Transcrição/antagonistas & inibidores , Triazóis/farmacologia , Ubiquitinação
9.
Cancer Cell ; 29(6): 846-858, 2016 06 13.
Artigo em Inglês | MEDLINE | ID: mdl-27238081

RESUMO

Androgen receptor (AR) signaling is a key driver of prostate cancer (PC). While androgen-deprivation therapy is transiently effective in advanced disease, tumors often progress to a lethal castration-resistant state (CRPC). We show that recurrent PC-driver mutations in speckle-type POZ protein (SPOP) stabilize the TRIM24 protein, which promotes proliferation under low androgen conditions. TRIM24 augments AR signaling, and AR and TRIM24 co-activated genes are significantly upregulated in CRPC. Expression of TRIM24 protein increases from primary PC to CRPC, and both TRIM24 protein levels and the AR/TRIM24 gene signature predict disease recurrence. Analyses in CRPC cells reveal that the TRIM24 bromodomain and the AR-interacting motif are essential to support proliferation. These data provide a rationale for therapeutic TRIM24 targeting in SPOP mutant and CRPC patients.


Assuntos
Proteínas de Transporte/genética , Proteínas Nucleares/genética , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias da Próstata/genética , Receptores Androgênicos/genética , Proteínas Repressoras/genética , Animais , Proteínas de Transporte/química , Proteínas de Transporte/metabolismo , Proliferação de Células , Progressão da Doença , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Transplante de Neoplasias , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Neoplasias de Próstata Resistentes à Castração/metabolismo , Neoplasias de Próstata Resistentes à Castração/patologia , Receptores Androgênicos/química , Receptores Androgênicos/metabolismo , Transdução de Sinais
10.
Cell Rep ; 11(4): 564-76, 2015 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-25892239

RESUMO

Understanding the molecular pathways that contribute to the aggressive behavior of HER2-positive breast cancers may aid in the development of novel therapeutic interventions. Here, we show that CDCP1 and HER2 are frequently co-overexpressed in metastatic breast tumors and associated with poor patient prognosis. HER2 and CDCP1 co-overexpression leads to increased transformation ability, cell migration, and tumor formation in vivo, and enhanced HER2 activation and downstream signaling in different breast cancer cell lines. Mechanistically, we demonstrate that CDCP1 binds to HER2 through its intracellular domain, thereby increasing HER2 interaction with the non-receptor tyrosine kinase c-SRC (SRC), leading to trastuzumab resistance. Taken together, our findings establish that CDCP1 is a modulator of HER2 signaling and a biomarker for the stratification of breast cancer patients with poor prognosis. Our results also provide a rationale for therapeutic targeting of CDCP1 in HER2-positive breast cancer patients.


Assuntos
Antígenos CD/metabolismo , Neoplasias da Mama/metabolismo , Carcinogênese/metabolismo , Moléculas de Adesão Celular/metabolismo , Resistencia a Medicamentos Antineoplásicos , Proteínas de Neoplasias/metabolismo , Receptor ErbB-2/metabolismo , Animais , Antígenos CD/genética , Antígenos de Neoplasias , Antineoplásicos/farmacologia , Neoplasias da Mama/genética , Carcinogênese/genética , Moléculas de Adesão Celular/genética , Feminino , Humanos , Células MCF-7 , Camundongos , Proteínas de Neoplasias/genética , Ligação Proteica , Receptor ErbB-2/genética , Trastuzumab/farmacologia , Quinases da Família src/metabolismo
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