RESUMO
Yes-associated protein (YAP) and TAZ (WW domain containing transcription regulator 1, or WWTR1) are paralog transcriptional regulators, able to integrate mechanical, metabolic, and signaling inputs to regulate cell growth and differentiation during development and neoplastic progression. YAP and TAZ hold common and distinctive structural features, reflecting only partially overlapping regulatory mechanisms. The two paralogs interact with both shared and specific transcriptional partners and control nonidentical transcriptional programs. Although most of the available literature considers YAP and TAZ as functionally redundant, they play distinctive or even contrasting roles in different contexts. The issue of their divergent roles is currently underexplored but holds fundamental implications for mechanistic and translational studies. Here, we aim to review the available literature on the biological functions of YAP and TAZ, highlighting differential roles that distinguish these two paralogues.
Assuntos
Transdução de Sinais , Diferenciação Celular , Proliferação de CélulasRESUMO
Aberrant reactivation of embryonic pathways is a common feature of cancer. RUNX2 is a transcription factor crucial during embryogenesis that is aberrantly reactivated in many tumors, including thyroid and breast cancer, where it promotes aggressiveness and metastatic spreading. Currently, the mechanisms driving RUNX2 expression in cancer are still largely unknown. Here we showed that RUNX2 transcription in thyroid and breast cancer requires the cooperation of three distantly located enhancers (ENHs) brought together by chromatin three-dimensional looping. We showed that BRD4 controls RUNX2 by binding to the newly identified ENHs and we demonstrated that the anti-proliferative effects of bromodomain inhibitors (BETi) is associated with RUNX2 transcriptional repression. We demonstrated that each RUNX2 ENH is potentially controlled by a distinct set of TFs and we identified c-JUN as the principal pivot of this regulatory platform. We also observed that accumulation of genetic mutations within these elements correlates with metastatic behavior in human thyroid tumors. Finally, we identified RAINs, a novel family of ENH-associated long non-coding RNAs, transcribed from the identified RUNX2 regulatory unit. Our data provide a new model to explain how RUNX2 expression is reactivated in thyroid and breast cancer and how cancer-driving signaling pathways converge on the regulation of this gene.
Assuntos
Subunidade alfa 1 de Fator de Ligação ao Core/genética , Regulação Neoplásica da Expressão Gênica , Proteínas Nucleares/genética , Proteínas Proto-Oncogênicas c-jun/genética , Fatores de Transcrição/genética , Western Blotting , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Proteínas de Ciclo Celular , Linhagem Celular Tumoral , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Elementos Facilitadores Genéticos/genética , Humanos , Células MCF-7 , Proteínas Nucleares/metabolismo , Ligação Proteica , Proteínas Proto-Oncogênicas c-jun/metabolismo , Interferência de RNA , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/metabolismo , Neoplasias da Glândula Tireoide/patologia , Fatores de Transcrição/metabolismoAssuntos
Adenocarcinoma de Pulmão/genética , Biomarcadores Tumorais , Genômica , Prolina Dioxigenases do Fator Induzível por Hipóxia/genética , Mutação , Proteínas Proto-Oncogênicas p21(ras)/genética , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/metabolismo , Adenocarcinoma de Pulmão/patologia , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Gerenciamento Clínico , Suscetibilidade a Doenças , Técnicas de Inativação de Genes , Genômica/métodos , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Prolina Dioxigenases do Fator Induzível por Hipóxia/metabolismo , Modelos Biológicos , Terapia de Alvo MolecularRESUMO
Non-small-cell lung carcinoma (NSCLC) is the most common lung cancer and one of the pioneer tumors in which immunotherapy has radically changed patients' outcomes. However, several issues are emerging and their implementation is required to optimize immunotherapy-based protocols. In this work, we investigate the ability of the Bromodomain and Extra-Terminal protein inhibitors (BETi) to stimulate a proficient anti-tumor immune response toward NSCLC. By using in vitro, ex-vivo, and in vivo models, we demonstrate that these epigenetic drugs specifically enhance Natural Killer (NK) cell cytotoxicity. BETi down-regulate a large set of NK inhibitory receptors, including several immune checkpoints (ICs), that are direct targets of the transcriptional cooperation between the BET protein BRD4 and the transcription factor SMAD3. Overall, BETi orchestrate an epigenetic reprogramming that leads to increased recognition of tumor cells and the killing ability of NK cells. Our results unveil the opportunity to exploit and repurpose these drugs in combination with immunotherapy.
Assuntos
Antineoplásicos , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Antineoplásicos/farmacologia , Células Matadoras Naturais , Proteína Smad3/genética , Proteína Smad3/metabolismo , Proteínas que Contêm BromodomínioRESUMO
Long non-coding RNAs (lncRNAs) are transcripts without coding potential that are pervasively expressed from the genome and have been increasingly reported to play crucial roles in all aspects of cell biology. They have been also heavily implicated in cancer development and progression, with both oncogenic and tumor suppressor functions. In this work, we identified and characterized a novel lncRNA, TAZ-AS202, expressed from the TAZ genomic locus and exerting pro-oncogenic functions in non-small cell lung cancer. TAZ-AS202 expression is under the control of YAP/TAZ-containing transcriptional complexes. We demonstrated that TAZ-AS202 is overexpressed in lung cancer tissue, compared with surrounding lung epithelium. In lung cancer cell lines TAZ-AS202 promotes cell migration and cell invasion. TAZ-AS202 regulates the expression of a set of genes belonging to cancer-associated pathways, including WNT and EPH-Ephrin signaling. The molecular mechanism underlying TAZ-AS202 function does not involve change of TAZ expression or activity, but increases the protein level of the transcription factor E2F1, which in turn regulates the expression of a large set of target genes, including the EPHB2 receptor. Notably, the silencing of both E2F1 and EPHB2 recapitulates TAZ-AS202 silencing cellular phenotype, indicating that they are essential mediators of its activity. Overall, this work unveiled a new regulatory mechanism that, by increasing E2F1 protein, modifies the non-small cell lung cancer cells transcriptional program, leading to enhanced aggressiveness features. The TAZ-AS202/E2F1/EPHB2 axis may be the target for new therapeutic strategies.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , RNA Longo não Codificante , Humanos , Neoplasias Pulmonares/patologia , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Carcinoma Pulmonar de Células não Pequenas/genética , Fator de Transcrição E2F1/genética , Fator de Transcrição E2F1/metabolismo , Efrinas/genética , Efrinas/metabolismo , Linhagem Celular Tumoral , Pulmão/metabolismo , Regulação Neoplásica da Expressão Gênica/genéticaRESUMO
EGLN1, EGLN2 and EGLN3 are proline hydroxylase whose main function is the regulation of the HIF factors. They work as oxygen sensors and are the main responsible of HIFα subunits degradation in normoxia. Being their activity strictly oxygen-dependent, when oxygen tension lowers, their control on HIFα is released, leading to activation of systemic and cellular response to hypoxia. However, EGLN family members activity is not limited to HIF modulation, but it includes the regulation of essential mechanisms for cell survival, cell cycle metabolism, proliferation and transcription. This is due to their reported hydroxylase activity on a number of non-HIF targets and sometimes to hydroxylase-independent functions. For these reasons, EGLN enzymes appear fundamental for development and progression of different cancer types, playing either a tumor-suppressive or a tumor-promoting role, according to EGLN isoform and to tumor context. Notably, EGLN1, the most studied isoform, has been shown to have also a central role in tumor micro-environment modulation, mediating CAF activation and impairing HIF1α -related angiogenesis, thus covering an important function in cancer metastasis promotion. Considering the recent knowledge acquired on EGLNs, the possibility to target these enzymes for cancer treatment is emerging. However, due to their multifaceted and controversial roles in different cancer types, the use of EGLN inhibitors as anti-cancer drugs should be carefully evaluated in each context.
Assuntos
Neoplasias , Prolil Hidroxilases , Humanos , Hipóxia/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia , Prolina Dioxigenases do Fator Induzível por Hipóxia , Neoplasias/tratamento farmacológico , Neoplasias/genética , Oxigênio/metabolismo , Pró-Colágeno-Prolina Dioxigenase/metabolismo , Microambiente TumoralRESUMO
Lung cancer is the leading cause of cancer-related human death. It is a heterogeneous disease, classified in two main histotypes, small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC), which is further subdivided into squamous-cell carcinoma (SCC) and adenocarcinoma (AD) subtypes. Despite the introduction of innovative therapeutics, mainly designed to specifically treat AD patients, the prognosis of lung cancer remains poor. In particular, available treatments for SCLC and SCC patients are currently limited to platinum-based chemotherapy and immune checkpoint inhibitors. In this work, we used an integrative approach to identify novel vulnerabilities in lung cancer. First, we compared the data from a CRISPR/Cas9 dependency screening performed in our laboratory with Cancer Dependency Map Project data, essentiality comprising information on 73 lung cancer cell lines. Next, to identify relevant therapeutic targets, we integrated dependency data with pharmacological data and TCGA gene expression information. Through this analysis, we identified CSNK1A1, KDM2A, and LTB4R2 as relevant druggable essentiality genes in lung cancer. We validated the antiproliferative effect of genetic or pharmacological inhibition of these genes in two lung cancer cell lines. Overall, our results identified new vulnerabilities associated with different lung cancer histotypes, laying the basis for the development of new therapeutic strategies.
RESUMO
Understanding the molecular mechanisms driving resistance to anti-cancer drugs is both a crucial step to define markers of response to therapy and a clinical need in many cancer settings. YAP and TAZ transcriptional cofactors behave as oncogenes in different cancer types. Deregulation of YAP/TAZ expression or alterations in components of the multiple signaling pathways converging on these factors are important mechanisms of resistance to chemotherapy, target therapy and hormone therapy. Moreover, response to immunotherapy may also be affected by YAP/TAZ activities in both tumor and microenvironment cells. For these reasons, various compounds inhibiting YAP/TAZ function by different direct and indirect mechanisms have been proposed as a mean to counter-act drug resistance in cancer. A particularly promising approach may be to simultaneously target both YAP/TAZ expression and their transcriptional activity through BET inhibitors.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Antineoplásicos/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Transativadores/metabolismo , Fatores de Transcrição/metabolismo , Microambiente Tumoral/efeitos dos fármacos , Proteínas Adaptadoras de Transdução de Sinal/genética , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Redes e Vias Metabólicas/efeitos dos fármacos , Redes e Vias Metabólicas/genética , Neoplasias/genética , Neoplasias/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Transativadores/genética , Fatores de Transcrição/genética , Proteínas com Motivo de Ligação a PDZ com Coativador Transcricional , Microambiente Tumoral/genética , Proteínas de Sinalização YAPRESUMO
Enhancer (ENH)-associated long noncoding RNAs (lncRNA) are a peculiar class of RNAs produced by transcriptionally active ENHs, owning potential gene-regulatory function. Here, we characterized RAIN, a novel ENH-associated lncRNA. Analysis of RAIN expression in a retrospective cohort of human thyroid cancers showed that the expression of this lncRNA is restricted to cancer cells and strongly correlates with the expression of the cancer-promoting transcription factor RUNX2. We showed that RAIN, serving as a cis-regulatory element, promotes RUNX2 expression by two mechanisms. Binding WDR5 and facilitating its localization on the RUNX2 promoter, RAIN modifies the transcriptional status of the RUNX2 locus facilitating transcription initiation. In parallel, RAIN acts as decoy for negative elongation factor complex, restraining its inhibitory function on transcription elongation. In both thyroid and breast cancer cells, RAIN promotes oncogenic features. Using RNA-sequencing profiling, we showed that RAIN orchestrates the expression of a network of cancer-promoting transcription regulators, suggesting that RAIN affects cancer cell phenotype by coordinating the expression of a complex transcriptional network. IMPLICATIONS: Our data contribute to understand lncRNA function in gene regulation and to consolidate their role in cancer.
Assuntos
Neoplasias da Mama/genética , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/efeitos adversos , RNA Longo não Codificante/genética , Neoplasias da Glândula Tireoide/genética , Técnicas de Cultura de Células , Linhagem Celular Tumoral , Feminino , Humanos , MasculinoRESUMO
Inhibitors of BET proteins (BETi) are anti-cancer drugs that have shown efficacy in pre-clinical settings and are currently in clinical trials for different types of cancer, including non-small cell lung cancer (NSCLC). Currently, no predictive biomarker is available to identify patients that may benefit from this treatment. To uncover the mechanisms of resistance to BETi, we performed a genome-scale CRISPR/Cas9 screening in lung cancer cells. We identified three Hippo pathway genes, LATS2, TAOK1, and NF2, as key determinants for sensitivity to BETi. The knockout of these genes induces resistance to BETi, by promoting TAZ nuclear localization and transcriptional activity. Conversely, TAZ expression promotes resistance to these drugs. We also showed that TAZ, YAP, and their partner TEAD are direct targets of BRD4 and that treatment with BETi downregulates their expression. Noticeably, molecular alterations in one or more of these genes are present in a large fraction of NSCLC patients and TAZ amplification or overexpression correlates with a worse outcome in lung adenocarcinoma. Our data define the central role of Hippo pathway in mediating resistance to BETi and provide a rationale for using BETi to counter-act YAP/TAZ-mediated pro-oncogenic activity.