RESUMEN
Cancer cells undergo transcriptional reprogramming to drive tumor progression and metastasis. Using cancer cell lines and patient-derived tumor organoids, we demonstrate that loss of the negative elongation factor (NELF) complex inhibits breast cancer development through downregulating epithelial-mesenchymal transition (EMT) and stemness-associated genes. Quantitative multiplexed Rapid Immunoprecipitation Mass spectrometry of Endogenous proteins (qPLEX-RIME) further reveals a significant rewiring of NELF-E-associated chromatin partners as a function of EMT and a co-option of NELF-E with the key EMT transcription factor SLUG. Accordingly, loss of NELF-E leads to impaired SLUG binding on chromatin. Through integrative transcriptomic and genomic analyses, we identify the histone acetyltransferase, KAT2B, as a key functional target of NELF-E-SLUG. Genetic and pharmacological inactivation of KAT2B ameliorate the expression of EMT markers, phenocopying NELF ablation. Elevated expression of NELF-E and KAT2B is associated with poorer prognosis in breast cancer patients, highlighting the clinical relevance of our findings. Taken together, we uncover a crucial role of the NELF-E-SLUG-KAT2B epigenetic axis in breast cancer carcinogenesis.
Asunto(s)
Neoplasias de la Mama , Femenino , Humanos , Neoplasias de la Mama/patología , Carcinogénesis/genética , Línea Celular Tumoral , Cromatina , Epigénesis Genética , Transición Epitelial-Mesenquimal/genética , Regulación Neoplásica de la Expresión Génica , Factores de Transcripción p300-CBP/metabolismo , Factores de Transcripción de la Familia Snail/metabolismo , Factores de Transcripción/metabolismoRESUMEN
Meiosis increases genetic diversity in offspring by generating genetically unique haploid gametes with reshuffled chromosomes. This process requires a specialized set of meiotic proteins, which facilitate chromosome recombination and segregation. However, re-expression of meiotic proteins in mitosis can have catastrophic oncogenic consequences and aberrant expression of meiotic proteins is a common occurrence in human tumors. Mechanistically, re-activation of meiotic genes in cancer promotes oncogenesis likely because cancers-conversely to healthy mitosis-are fueled by genetic instability which promotes tumor evolution, and evasion of immune response and treatment pressure. In this review, we explore similarities between meiotic and cancer cells with a particular focus on the oncogenic activation of meiotic genes in cancer. We emphasize the role of histones and their modifications, DNA methylation, genome organization, R-loops and the availability of distal enhancers.
Asunto(s)
Meiosis , Neoplasias , Humanos , Meiosis/genética , Cromosomas , Histonas/genética , Expresión Génica , Neoplasias/genéticaRESUMEN
Meiosis facilitates diversity across individuals and serves as a major driver of evolution. However, understanding how meiosis begins is complicated by fundamental differences that exist between sexes and species. Fundamental meiotic research is further hampered by a current lack of human meiotic cells lines. Consequently, much of what we know relies on data from model organisms. However, contextualising findings from yeast, worms, flies and mice can be challenging, due to marked differences in both nomenclature and the relative timing of meiosis. In this review, we set out to combine current knowledge of signalling and transcriptional pathways that control meiosis initiation across the sexes in a variety of organisms. Furthermore, we highlight the emerging links between meiosis initiation and oncogenesis, which might explain the frequent re-expression of normally silent meiotic genes in a variety of human cancers.