HOXA transcript at the distal tip (HOTTIP), a long noncoding RNA, is upregulated in pancreatic ductal adenocarcinoma (PDAC), but the HOTTIP-mediated oncogenic pathway is not fully understood. We identified canonical HOTTIP-HOXA13 targets, CYP26B1, CLIC5, CHI3L1 and UCP2-responsible for cell growth and cell invasion. Genome-wide analysis revealed that 38% of HOTTIP-regulated genes contain H3K4me3 and HOTTIP enrichment at their promoters, without HOXA13 binding. HOTTIP complexes with WDR5-MLL1 to trans-activate oncogenic proteins CYB5R2, SULT1A1, KIF26A, SLC1A4, and TSC22D1 by directly inducing H3K4me3 at their promoters. The WDR5, MLL1, and H3K4me3 levels at their promoters and their expression levels are sensitive to HOTTIP expression. These results indicate the importance of the noncanonical trans-acting HOTTIP-WDR5-MLL1 pathway in the HOTTIP regulatory mechanism by promoting oncogenic protein expression. Furthermore, HOTTIP is regulated by miR-497 in PDAC cells, but HOTTIP is negatively correlated with miR-497 levels in PDAC tissues. In conclusion, HOTTIP is upregulated in PDAC due to the loss of the inhibitory miR-497; HOTTIP promotes PDAC progression through the canonical HOTTIP-HOXA13 axis. A novel noncanonical trans-acting HOTTIP-WDR5-MLL1-H3K4me3 pathway is also delineated.

中文翻译：

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异位 HOTTIP 表达诱导非典型反式激活途径，促进胰腺导管腺癌的生长和侵袭。


HOXA 远端转录本 (HOTTIP) 是一种长非编码 RNA，在胰腺导管腺癌 (PDAC) 中表达上调，但 HOTTIP 介导的致癌途径尚不完全清楚。我们确定了负责细胞生长和细胞侵袭的经典 HOTTIP-HOXA13 靶标、CYP26B1、CLIC5、CHI3L1 和 UCP2。全基因组分析显示，38% 的 HOTTIP 调控基因在其启动子处含有 H3K4me3 和 HOTTIP 富集，但没有 HOXA13 结合。 HOTTIP 与 WDR5-MLL1 复合，通过在启动子处直接诱导 H3K4me3 来反式激活致癌蛋白 CYB5R2、SULT1A1、KIF26A、SLC1A4 和 TSC22D1。 WDR5、MLL1 和 H3K4me3 启动子的水平及其表达水平对 HOTTIP 表达敏感。这些结果表明非经典反式作用 HOTTIP-WDR5-MLL1 通路通过促进致癌蛋白表达在 HOTTIP 调节机制中的重要性。此外，HOTTIP 在 PDAC 细胞中受 miR-497 调节，但 HOTTIP 与 PDAC 组织中 miR-497 水平呈负相关。总之，由于抑制性 miR-497 的缺失，HOTTIP 在 PDAC 中上调； HOTTIP 通过典型的 HOTTIP-HOXA13 轴促进 PDAC 进展。还描述了一种新的非经典反式作用 HOTTIP-WDR5-MLL1-H3K4me3 途径。