Ectopic HOTTIP Expression Induces Non-canonical Transactivation Pathways to Promote Growth and Invasiveness in Pancreatic Ductal Adenocarcinoma
Ectopic HOTTIP Expression Induces Non-canonical Transactivation Pathways to Promote Growth and Invasiveness in Pancreatic Ductal Adenocarcinoma
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DOI：
10.1101/812800
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发表时间：
2019-10
期刊：
影响因子：
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通讯作者：
C. Wong;C. Li;Qifang He;Stephen Lam Chan;J. Tong;K. To;Yangchao Chen
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文献类型：
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作者：
C. Wong;C. Li;Qifang He;Stephen Lam Chan;J. Tong;K. To;Yangchao Chen
LncRNA HOTTIP（远端末端的HOXA转录物）在胰腺导管腺癌（PDAC）中上调。然而，HOTTIP介导的致癌途径尚未完全了解。我们确定了典型的HOTTIP-HOXA 13靶点：CYP 26 B1，CLIC 5，CHI 3L 1和UCP 2，它们负责细胞生长和细胞侵袭。重要的是，全基因组分析显示，38%的HOTTIP调控的基因在其启动子处含有H3 K4 me 3和HOTTIP富集，而没有HOXA 13结合。HOTTIP与WDR 5-MLL 1复合，通过直接触发其启动子处的H3 K4 me 3来反式激活致癌蛋白CYB 5 R2、SULT 1A 1、KIF 26 A、SLC 1A 4和TSC 22 D1。WDR 5、MLL 1和H3 K4 me 3在其启动子处的水平及其表达水平对HOTTIP过表达和敲低敏感。提示HOTTIP-WDR 5-MLL 1通路在HOTTIP调控机制中起重要作用，可能通过促进癌基因蛋白的表达而发挥作用。此外，我们剖析了HOTTIP在PDAC中受miR-497调控的机制。PDAC人体组织分析也显示HOTTIP与miR-497水平呈负相关。我们的研究结果表明，HOTTIP，由于抑制性miR-497的丢失而在PDAC中上调，通过经典HOTTIP-HOXA 13轴和新的非经典反式作用HOTTIP-WDR 5-MLL 1-H3 K4 me 3途径促进PDAC进展。
LncRNA HOTTIP (HOXA transcript at the distal tip) is upregulated in pancreatic ductal adenocarcinoma (PDAC). However, oncogenic pathway mediated by HOTTIP is not fully understood. We identified canonical HOTTIP-HOXA13 targets: CYP26B1, CLIC5, CHI3L1 and UCP2 which were responsible for cell growth and cell invasion. Importantly, genome-wide analysis revealed that 38% of the genes regulated by HOTTIP contained H3K4me3 and HOTTIP enrichment at their promoters, without HOXA13 binding. HOTTIP complexed with WDR5-MLL1 to trans-activate oncogenic proteins CYB5R2, SULT1A1, KIF26A, SLC1A4 and TSC22D1 through directly triggering H3K4me3 at their promoters. The WDR5, MLL1 and H3K4me3 levels at their promoters and their expression levels were sensitive to HOTTIP overexpression and knockdown. These suggested the importance of non-canonical trans-acting HOTTIP-WDR5-MLL1 pathway in HOTTIP-regulatory mechanism by promoting the expression of oncogenic proteins. Furthermore, we dissected the mechanism by which HOTTIP was regulated by miR-497 in PDAC. Analysis of PDAC human tissues also revealed that HOTTIP was negatively correlated with miR-497 level. Our findings demonstrated that HOTTIP, upregulated in PDAC due to the loss of inhibitory miR-497, promoted PDAC progression through canonical HOTTIP-HOXA13 axis and a novel non-canonical trans-acting HOTTIP-WDR5-MLL1-H3K4me3 pathway.