Bhan Arunoday, Deb Paromita, Shihabeddin Nadine, Ansari Khairul I, Brotto Marco, Mandal Subhrangsu S
Department of Chemistry and Biochemistry, The University of Texas at Arlington, Arlington, TX 76019, United States.
College of Nursing and Health Innovation, The University of Texas at Arlington, Arlington, TX 76019, United States.
Gene. 2017 Sep 20;629:16-28. doi: 10.1016/j.gene.2017.07.069. Epub 2017 Jul 26.
Hypoxia signaling plays a critical role in tumor growth, angiogenesis, metastasis cancer, and aging. Under hypoxia, hypoxia-inducible factors (HIFs) are stabilized and they coordinate the process of hypoxia-induced gene expression and cell signaling leading to increased tumor growth. Recent studies indicate that non-coding RNAs which are closely associated with cancer are abnormally expressed under hypoxia. Here, we have investigated the transcriptional regulation of a cancer associated long non-coding RNA (lncRNA), HOTAIR, under hypoxic conditions. Our studies demonstrate that HOTAIR expression is upregulated under hypoxia in colon cancer and several other types of cancer cells. HOTAIR transcription is regulated by HIF1α which binds to the hypoxia response elements (HRE) present in the HOTAIR promoter under hypoxia. HIF1α knockdown results in decreased HOTAIR expression under hypoxia. Along with HIF1α, histone methylases MLL1 and histone acetylase p300 are enriched at the HOTAIR promoter under hypoxia. The levels of H3K4-trimethylation and histone acetylation are also enriched at the HOTAIR promoter. Furthermore, knockdown of MLL1 downregulated the hypoxia-induced HOTAIR expression, indicating key roles of MLL1 in hypoxia-induced HOTAIR expression. Overall, our studies demonstrate that histone methyl-transferase MLL1 coordinates with HIF1α and histone acetyltransferase p300 and regulate hypoxia-induced HOTAIR expression. The hypoxia-induced upregulation of HOTAIR expression may contribute to its roles in tumorigenesis.
缺氧信号传导在肿瘤生长、血管生成、癌症转移和衰老过程中起着关键作用。在缺氧条件下，缺氧诱导因子（HIFs）会稳定下来，它们协调缺氧诱导的基因表达和细胞信号传导过程，从而导致肿瘤生长增加。最近的研究表明，与癌症密切相关的非编码RNA在缺氧条件下会异常表达。在此，我们研究了一种与癌症相关的长链非编码RNA（lncRNA）——HOTAIR在缺氧条件下的转录调控。我们的研究表明，在结肠癌和其他几种癌细胞中，缺氧会使HOTAIR表达上调。HOTAIR的转录受HIF1α调控，在缺氧条件下，HIF1α会与HOTAIR启动子中存在的缺氧反应元件（HRE）结合。敲低HIF1α会导致缺氧条件下HOTAIR表达降低。在缺氧条件下，组蛋白甲基转移酶MLL1和组蛋白乙酰转移酶p300会在HOTAIR启动子处富集。HOTAIR启动子处的H3K4三甲基化水平和组蛋白乙酰化水平也会升高。此外，敲低MLL1会下调缺氧诱导的HOTAIR表达，表明MLL1在缺氧诱导的HOTAIR表达中起关键作用。总体而言，我们的研究表明，组蛋白甲基转移酶MLL1与HIF1α和组蛋白乙酰转移酶p300协同作用，调节缺氧诱导的HOTAIR表达。缺氧诱导的HOTAIR表达上调可能有助于其在肿瘤发生中的作用。
