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bioRxiv · 10.1101/812800

Ectopic HOTTIP Expression Induces Non-canonical Transactivation Pathways to Promote Growth and Invasiveness in Pancreatic Ductal Adenocarcinoma

Wong, C. H.·Li, C. H.·He, Q.·Chan, S. L.·Tong, J. H.-M.·To, K.-F.·Chen, Y.
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Abstract

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.

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Wong, C. H., Li, C. H., He, Q., Chan, S. L., Tong, J. H.-M., To, K.-F., Chen, Y.. 2019-10-21. Ectopic HOTTIP Expression Induces Non-canonical Transactivation Pathways to Promote Growth and Invasiveness in Pancreatic Ductal Adenocarcinoma. https://doi.org/10.1101/812800

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