RESUMEN
Organelles use specialized molecules to regulate their essential cellular processes. However, systematically elucidating the subcellular distribution and function of molecules such as long non-coding RNAs (lncRNAs) in cellular homeostasis and diseases has not been fully achieved. Here, we reveal the diverse and abundant subcellular distribution of organelle-associated lncRNAs from mitochondria, lysosomes and endoplasmic reticulum. Among them, we identify the mitochondrially localized lncRNA growth-arrest-specific 5 (GAS5) as a tumour suppressor in maintaining cellular energy homeostasis. Mechanistically, energy-stress-induced GAS5 modulates mitochondrial tricarboxylic acid flux by disrupting metabolic enzyme tandem association of fumarate hydratase, malate dehydrogenase and citrate synthase, the canonical members of the tricarboxylic acid cycle. GAS5 negatively correlates with levels of its associated mitochondrial metabolic enzymes in tumours and benefits overall survival in individuals with breast cancer. Together, our detailed annotation of subcellular lncRNA distribution identifies a functional role for lncRNAs in regulating cellular metabolic homeostasis, highlighting organelle-associated lncRNAs as potential clinical targets to manipulate cellular metabolism and diseases.
Asunto(s)
Ciclo del Ácido Cítrico/fisiología , Mitocondrias/metabolismo , ARN Largo no Codificante/metabolismo , Animales , Neoplasias de la Mama/genética , Línea Celular Tumoral , Retículo Endoplásmico/metabolismo , Femenino , Homeostasis , Humanos , Lisosomas/metabolismo , Ratones , Ratones Endogámicos BALB C , Nutrientes , Orgánulos/metabolismo , ARN Neoplásico/genéticaRESUMEN
The human genome transcribes a large amount of non-coding RNAs, including long non-coding RNAs (lncRNAs) and microRNAs. LncRNAs and microRNAs have been shown to play a critical regulatory role in tumorigenesis and progression. Competitive endogenous RNAs (ceRNAs) affect other RNAs transcription through competitively binding to common microRNAs (miRNAs). MALAT1 is a typical lncRNA that is markedly up-regulated in breast cancer. However, current understanding of the involvement of MALAT1 in breast cancer development and prognosis remains unclear. In the present study, the expression of MALAT1 in clinical samples of breast cancer tissues was found to be significantly up-regulated that was consistent with the result based on the dataset of the Cancer Genome Atlas (TCGA) at cBioportal. A negative correlation between overall survival and the expression of MALAT1 was statistically significant in the group of diagnosis age below 60 or in the group of infiltrating ductal carcinoma analyzed by TCGA database, which declared that MALAT1 might be a potentially useful prognostic factor. Furthermore, the combination of bioinformatics prediction with experimental verifications indicated that lncRNA MALAT1 can regulate BLCAP mRNA expression through binding to miR-339-5p.