RESUMO
The androgen receptor (AR) plays a critical role in the development of the normal prostate as well as prostate cancer. Using an integrative transcriptomic analysis of prostate cancer cell lines and tissues, we identified ARLNC1 (AR-regulated long noncoding RNA 1) as an important long noncoding RNA that is strongly associated with AR signaling in prostate cancer progression. Not only was ARLNC1 induced by the AR protein, but ARLNC1 stabilized the AR transcript via RNA-RNA interaction. ARLNC1 knockdown suppressed AR expression, global AR signaling and prostate cancer growth in vitro and in vivo. Taken together, these data support a role for ARLNC1 in maintaining a positive feedback loop that potentiates AR signaling during prostate cancer progression and identify ARLNC1 as a novel therapeutic target.
Assuntos
Neoplasias da Próstata/genética , RNA Longo não Codificante/genética , Receptores Androgênicos/genética , Androgênios/genética , Androgênios/metabolismo , Linhagem Celular Tumoral , Progressão da Doença , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Próstata/fisiologia , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , RNA Longo não Codificante/metabolismo , Receptores Androgênicos/metabolismo , Transdução de SinaisRESUMO
Molecular classification of cancers into subtypes has resulted in an advance in our understanding of tumour biology and treatment response across multiple tumour types. However, to date, cancer profiling has largely focused on protein-coding genes, which comprise <1% of the genome. Here we leverage a compendium of 58,648 long noncoding RNAs (lncRNAs) to subtype 947 breast cancer samples. We show that lncRNA-based profiling categorizes breast tumours by their known molecular subtypes in breast cancer. We identify a cohort of breast cancer-associated and oestrogen-regulated lncRNAs, and investigate the role of the top prioritized oestrogen receptor (ER)-regulated lncRNA, DSCAM-AS1. We demonstrate that DSCAM-AS1 mediates tumour progression and tamoxifen resistance and identify hnRNPL as an interacting protein involved in the mechanism of DSCAM-AS1 action. By highlighting the role of DSCAM-AS1 in breast cancer biology and treatment resistance, this study provides insight into the potential clinical implications of lncRNAs in breast cancer.
Assuntos
Neoplasias da Mama/metabolismo , RNA Longo não Codificante/metabolismo , Antineoplásicos Hormonais/farmacologia , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Invasividade Neoplásica , RNA Longo não Codificante/genética , Receptores de Estrogênio , Tamoxifeno/farmacologiaRESUMO
MOTIVATION: Intra-tumor heterogeneity presents itself through the evolution of subclones during cancer progression. Although recent research suggests that this heterogeneity has clinical implications, in silico determination of the clonal subpopulations remains a challenge. RESULTS: We address this problem through a novel combinatorial method, named clonality inference in tumors using phylogeny (CITUP), that infers clonal populations and their frequencies while satisfying phylogenetic constraints and is able to exploit data from multiple samples. Using simulated datasets and deep sequencing data from two cancer studies, we show that CITUP predicts clonal frequencies and the underlying phylogeny with high accuracy. AVAILABILITY AND IMPLEMENTATION: CITUP is freely available at: http://sourceforge.net/projects/citup/. CONTACT: cenk@sfu.ca SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.