Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis.
Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis.
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大型干预非编码rna （lincRNAs）在基因组中广泛转录，但它们在人类疾病中的潜在参与尚不清楚。最近关于剂量补偿、印迹和同质基因表达的研究表明，单个lincrna可以作为DNA和特定染色质重塑活动之间的界面。本研究表明，在乳腺癌进展过程中，HOX基因座中的lincrna发生系统性失调。被称为HOTAIR的lincRNA在原发性乳腺肿瘤和转移中表达增加，而HOTAIR在原发性肿瘤中的表达水平是最终转移和死亡的有力预测因子。在上皮癌细胞中，HOTAIR的强迫表达诱导多梳抑制复合体2 （Polycomb suppressuppressicomplex 2, PRC2）的全基因组重靶向，使其占据模式更类似于胚胎成纤维细胞，导致组蛋白H3赖氨酸27甲基化、基因表达改变，并以依赖于PRC2的方式增加癌症的侵袭性和转移。相反，HOTAIR的缺失可以抑制癌症的侵袭性，特别是在PRC2活性过高的细胞中。这些发现表明，lincRNAs在调节癌症表观基因组中发挥积极作用，可能是癌症诊断和治疗的重要靶点。
Large intervening noncoding RNAs (lincRNAs) are pervasively transcribed in the genome yet their potential involvement in human disease is not well understood. Recent studies of dosage compensation, imprinting, and homeotic gene expression suggest that individual lincRNAs can function as the interface between DNA and specific chromatin remodeling activities. Here we show that lincRNAs in the HOX loci become systematically dysregulated during breast cancer progression. The lincRNA termed HOTAIR is increased in expression in primary breast tumors and metastases, and HOTAIR expression level in primary tumors is a powerful predictor of eventual metastasis and death. Enforced expression of HOTAIR in epithelial cancer cells induced genome-wide re-targeting of Polycomb Repressive Complex 2 (PRC2) to an occupancy pattern more resembling embryonic fibroblasts, leading to altered histone H3 lysine 27 methylation, gene expression, and increased cancer invasiveness and metastasis in a manner dependent on PRC2. Conversely, loss of HOTAIR can inhibit cancer invasiveness, particularly in cells that possess excessive PRC2 activity. These findings suggest that lincRNAs play active roles in modulating the cancer epigenome and may be important targets for cancer diagnosis and therapy.
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