RESUMO
Transcriptional networks are critical for the establishment of tissue-specific cellular states in health and disease, including cancer. Yet, the transcriptional circuits that control carcinogenesis remain poorly understood. Here we report that Kruppel like factor 6 (KLF6), a transcription factor of the zinc finger family, regulates lipid homeostasis in clear cell renal cell carcinoma (ccRCC). We show that KLF6 supports the expression of lipid metabolism genes and promotes the expression of PDGFB, which activates mTOR signalling and the downstream lipid metabolism regulators SREBF1 and SREBF2. KLF6 expression is driven by a robust super enhancer that integrates signals from multiple pathways, including the ccRCC-initiating VHL-HIF2A pathway. These results suggest an underlying mechanism for high mTOR activity in ccRCC cells. More generally, the link between super enhancer-driven transcriptional networks and essential metabolic pathways may provide clues to the mechanisms that maintain the stability of cell identity-defining transcriptional programmes in cancer.
Assuntos
Carcinogênese/genética , Carcinoma de Células Renais/genética , Neoplasias Renais/genética , Fator 6 Semelhante a Kruppel/metabolismo , Metabolismo dos Lipídeos/genética , Animais , Carcinoma de Células Renais/patologia , Linhagem Celular Tumoral , Proliferação de Células/genética , Elementos Facilitadores Genéticos/genética , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Células HEK293 , Humanos , Rim/patologia , Neoplasias Renais/patologia , Fator 6 Semelhante a Kruppel/genética , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos Nus , Camundongos SCID , Proteínas Proto-Oncogênicas c-sis/genética , Transdução de Sinais/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 2/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Tissue-specific transcriptional programs control most biological phenotypes, including disease states such as cancer. However, the molecular details underlying transcriptional specificity is largely unknown, hindering the development of therapeutic approaches. Here, we describe novel experimental reporter systems that allow interrogation of the endogenous expression of HIF2A, a critical driver of renal oncogenesis. Using a focused CRISPR-Cas9 library targeting chromatin regulators, we provide evidence that these reporter systems are compatible with high-throughput screening. Our data also suggests redundancy in the control of cancer type-specific transcriptional traits. Reporter systems such as those described here could facilitate large-scale mechanistic dissection of transcriptional programmes underlying cancer phenotypes, thus paving the way for novel therapeutic approaches.
Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Perfilação da Expressão Gênica/métodos , Genes Reporter/genética , Testes Genéticos/métodos , Ensaios de Triagem em Larga Escala/métodos , Sistemas CRISPR-Cas/genética , Carcinogênese/genética , Carcinoma de Células Renais/genética , Linhagem Celular Tumoral , Estudos de Viabilidade , Regulação Neoplásica da Expressão Gênica/genética , Técnicas de Introdução de Genes , Redes Reguladoras de Genes/genética , Células HEK293 , Humanos , Neoplasias Renais/genética , Transcrição GênicaRESUMO
Metastases, the spread of cancer cells to distant organs, cause the majority of cancer-related deaths. Few metastasis-specific driver mutations have been identified, suggesting aberrant gene regulation as a source of metastatic traits. However, how metastatic gene expression programs arise is poorly understood. Here, using human-derived metastasis models of renal cancer, we identify transcriptional enhancers that promote metastatic carcinoma progression. Specific enhancers and enhancer clusters are activated in metastatic cancer cell populations, and the associated gene expression patterns are predictive of poor patient outcome in clinical samples. We find that the renal cancer metastasis-associated enhancer complement consists of multiple coactivated tissue-specific enhancer modules. Specifically, we identify and functionally characterize a coregulatory enhancer cluster, activated by the renal cancer driver HIF2A and an NF-κB-driven lymphoid element, as a mediator of metastasis in vivo We conclude that oncogenic pathways can acquire metastatic phenotypes through cross-lineage co-option of physiologic epigenetic enhancer states.Significance: Renal cancer is associated with significant mortality due to metastasis. We show that in metastatic renal cancer, functionally important metastasis genes are activated via co-option of gene regulatory enhancer modules from distant developmental lineages, thus providing clues to the origins of metastatic cancer. Cancer Discov; 8(7); 850-65. ©2018 AACR.This article is highlighted in the In This Issue feature, p. 781.