Histone methylase MLL1 coordinates with HIF and regulate lncRNA HOTAIR expression under hypoxia
Histone methylase MLL1 coordinates with HIF and regulate lncRNA HOTAIR expression under hypoxia
复制标题
DOI：
10.1016/j.gene.2017.07.069
复制
发表时间：
2017-09-20
期刊：
影响因子：
3.5
通讯作者：
Mandal, Subhrangsu S.
中科院分区：
文献类型：
--
作者：
Bhan, Arunoday;Deb, Paromita;Mandal, Subhrangsu S.
缺氧信号传导在肿瘤生长、血管生成、癌症转移和衰老中起关键作用。在缺氧条件下，缺氧诱导因子（HIF）是稳定的，它们协调缺氧诱导的基因表达和细胞信号传导的过程，导致肿瘤生长增加。近年来的研究表明，与癌症密切相关的非编码RNA在缺氧条件下会发生异常表达。在这里，我们研究了在缺氧条件下，癌症相关的长非编码RNA（lncRNA），HOTAIR的转录调控。我们的研究表明，HOTAIR表达上调缺氧条件下，在结肠癌和其他几种类型的癌细胞。HOTAIR转录受HIF 1 α调节，HIF 1 α在缺氧条件下与HOTAIR启动子中存在的缺氧反应元件（HRE）结合。HIF 1a敲低导致缺氧条件下HOTAIR表达降低。在缺氧条件下，组蛋白甲基化酶ML 1和组蛋白乙酰化酶p300与HIF 1a一起沿着富集在HOTAIR启动子处。H3 K4-三甲基化和组蛋白乙酰化的水平也在HOTAIR启动子处富集。此外，敲低MLL 1下调缺氧诱导的HOTAIR表达，表明MLL 1在缺氧诱导的HOTAIR表达中的关键作用。总之，我们的研究表明，组蛋白甲基转移酶MLL 1与HIF 1a和组蛋白乙酰转移酶p300协调，并调节缺氧诱导的HOTAIR表达。缺氧诱导的HOTAIR表达上调可能与其在肿瘤发生中的作用有关。
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 HIF1 alpha which binds to the hypoxia response elements (HRE) present in the HOTAIR promoter under hypoxia. HIF1a knockdown results in decreased HOTAIR expression under hypoxia. Along with HIF1a, 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 HIF1a and histone acetyltransferase p300 and regulate hypoxia-induced HOTAIR expression. The hypoxia-induced upregulation of HOTAIR expression may contribute to its roles in tumorigenesis.