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1.
Blood ; 142(1): 44-61, 2023 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-37023372

RESUMO

In chronic lymphocytic leukemia (CLL), epigenetic alterations are considered to centrally shape the transcriptional signatures that drive disease evolution and underlie its biological and clinical subsets. Characterizations of epigenetic regulators, particularly histone-modifying enzymes, are very rudimentary in CLL. In efforts to establish effectors of the CLL-associated oncogene T-cell leukemia 1A (TCL1A), we identified here the lysine-specific histone demethylase KDM1A to interact with the TCL1A protein in B cells in conjunction with an increased catalytic activity of KDM1A. We demonstrate that KDM1A is upregulated in malignant B cells. Elevated KDM1A and associated gene expression signatures correlated with aggressive disease features and adverse clinical outcomes in a large prospective CLL trial cohort. Genetic Kdm1a knockdown in Eµ-TCL1A mice reduced leukemic burden and prolonged animal survival, accompanied by upregulated p53 and proapoptotic pathways. Genetic KDM1A depletion also affected milieu components (T, stromal, and monocytic cells), resulting in significant reductions in their capacity to support CLL-cell survival and proliferation. Integrated analyses of differential global transcriptomes (RNA sequencing) and H3K4me3 marks (chromatin immunoprecipitation sequencing) in Eµ-TCL1A vs iKdm1aKD;Eµ-TCL1A mice (confirmed in human CLL) implicate KDM1A as an oncogenic transcriptional repressor in CLL which alters histone methylation patterns with pronounced effects on defined cell death and motility pathways. Finally, pharmacologic KDM1A inhibition altered H3K4/9 target methylation and revealed marked anti-B-cell leukemic synergisms. Overall, we established the pathogenic role and effector networks of KDM1A in CLL via tumor-cell intrinsic mechanisms and its impacts in cells of the microenvironment. Our data also provide rationales to further investigate therapeutic KDM1A targeting in CLL.


Assuntos
Leucemia Linfocítica Crônica de Células B , Humanos , Camundongos , Animais , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Histonas/metabolismo , Lisina , Estudos Prospectivos , Histona Desmetilases/genética , Histona Desmetilases/metabolismo , Microambiente Tumoral
2.
Adv Exp Med Biol ; 1255: 109-121, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32949394

RESUMO

Cancer is one of the leading causes of death worldwide and well known for its complexity. Cancer cells within the same tumor or from different tumors are highly heterogeneous. Furthermore, stromal and immune cells within tumor microenvironment interact with cancer cells to play important roles in how tumors progress and respond to different treatments. Recent advances in single cell technologies, especially massively parallel single cell sequencing, have made it possible to analyze cancer cells and cells in its tumor microenvironment in parallel with unprecedented high resolution. In this chapter, we will review recent developments in single cell sequencing technologies and their applications in cancer research. We will also explain how insights generated from single cell sequencing can be used to develop novel diagnostic and therapeutic approaches to conquer cancer.


Assuntos
Neoplasias/diagnóstico , Neoplasias/terapia , Análise de Sequência , Análise de Célula Única , Humanos , Neoplasias/genética , Microambiente Tumoral
3.
Mol Cancer Res ; 17(6): 1326-1337, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30760542

RESUMO

Lysine-specific demethylase 1 (LSD1) is a histone modifier that is highly overexpressed in lung adenocarcinoma, which results in aggressive tumor biology. Tumor cell proliferation and migration analysis after LSD1 inhibition in the lung adenocarcinoma cell line PC9, using the LSD1 inhibitor HCI-2509 and siRNA, demonstrated that LSD1 activity was essential for proliferation and migration capacities of tumor cells. Moreover, reduced proliferation rates after LSD1 inhibition were shown to be associated with a cell-cycle arrest of the tumor cells in the G2-M-phase. Expression profiling followed by functional classification and pathway analysis indicated prominent repression of the polo-like kinase 1 (PLK1) pathway upon LSD1 inhibition. In contrast, transient overexpression of exogenous PLK1 plasmid rescued the LSD1 inhibition-mediated downregulation of PLK1 pathway genes. Mechanistically, LSD1 directly regulates expression of PLK1 by binding to its promoter region that subsequently affects expression of its downstream target genes. Notably, using lung adenocarcinoma TCGA datasets a significant correlation between LSD1 and PLK1 along with its downstream targets was observed. Furthermore, the LSD1/PLK1 linkage was confirmed by IHC analysis in a clinical lung adenocarcinoma cohort (n = 43). Conclusively, this is the first study showing a direct transcriptional link between LSD1 and PLK1. IMPLICATIONS: These findings point to a role of LSD1 in regulating PLK1 and thus efficient G2-M-transition-mediating proliferation of tumor cells and suggest targeting the LSD1/PLK1 axis as a novel therapeutic approach for lung adenocarcinoma treatment.


Assuntos
Proteínas de Ciclo Celular/genética , Proliferação de Células/genética , Histona Desmetilases/genética , Mitose/genética , Proteínas Serina-Treonina Quinases/genética , Proteínas Proto-Oncogênicas/genética , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Pontos de Checagem do Ciclo Celular/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Regulação para Baixo/genética , Pontos de Checagem da Fase G2 do Ciclo Celular/genética , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Regiões Promotoras Genéticas/genética , RNA Interferente Pequeno/genética , Transcrição Gênica/genética , Quinase 1 Polo-Like
4.
Mol Oncol ; 12(11): 1965-1979, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30220105

RESUMO

Lung adenocarcinoma (LUAD) is the most prevalent subtype of non-small cell lung cancer. Despite the development of novel targeted and immune therapies, the 5-year survival rate is still only 21%, indicating the need for more efficient treatment regimens. Lysine-specific demethylase 1 (LSD1) is an epigenetic eraser that modifies histone 3 methylation status, and is highly overexpressed in LUAD. Using representative human cell culture systems and two autochthonous transgenic mouse models, we investigated inhibition of LSD1 as a novel therapeutic option for treating LUAD. The reversible LSD1 inhibitor HCI-2509 significantly reduced cell growth with an IC50 of 0.3-5 µmin vitro, which was linked to an enhancement of histone 3 lysine methylation. Most importantly, growth arrest, as well as inhibition of the invasion capacities, was independent of the underlying driver mutations. Subsequent expression profiling revealed that the cell cycle and replication machinery were prominently affected after LSD1 inhibition. In addition, our data provide evidence that LSD1 blockade significantly interferes with EGFR downstream signaling. Finally, our in vitro results were confirmed by preclinical therapeutic approaches, including the use of two autochthonous transgenic LUAD mouse models driven by either EGFR or KRAS mutations. Importantly, LSD1 inhibition resulted in significantly lower tumor formation and a strong reduction in tumor progression, which were independent of the underlying mutational background of the mouse models. Hence, our findings provide substantial evidence indicating that tumor growth of LUAD can be markedly decreased by HCI-2509 treatment, suggesting its use as a single agent maintenance therapy or combined therapeutical application in novel concerted drug approaches.


Assuntos
Adenocarcinoma de Pulmão/tratamento farmacológico , Inibidores Enzimáticos/farmacologia , Histona Desmetilases/antagonistas & inibidores , Neoplasias Pulmonares/tratamento farmacológico , Proteínas de Neoplasias/antagonistas & inibidores , Neoplasias Experimentais/tratamento farmacológico , Adenocarcinoma de Pulmão/enzimologia , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Animais , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Histona Desmetilases/genética , Histona Desmetilases/metabolismo , Humanos , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Transgênicos , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Neoplasias Experimentais/enzimologia , Neoplasias Experimentais/genética , Neoplasias Experimentais/patologia
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