LINC01198 activates Hippo signaling to stimulate IL-1β autocrine for driving vemurafenib resistance by associating with TAOK1/2 in melanoma

TL;DR

This study identifies LINC01198 as a key driver of resistance to the melanoma drug vemurafenib by activating a signaling pathway that promotes tumor survival.

Contribution

The study reveals a novel mechanism involving LINC01198 and the Hippo signaling pathway in vemurafenib resistance in melanoma.

Findings

LINC01198 is upregulated in vemurafenib-resistant melanoma cells.

LINC01198 activates Hippo signaling via TAOK1/2 to promote IL-1β secretion and drug resistance.

Loss of LINC01198 reduces melanoma resistance to vemurafenib.

Abstract

Vemurafenib (VEM) is an important targeted drug for treating melanoma harboring BRAF-V600E mutation. Despite its remarkable curative efficacy in early clinical treatment, most patients developed drug resistance within one year. Nevertheless, the critical factors driving vemurafenib resistance and mechanisms leading to treatment failure in melanoma are debating and inconclusive. In this study, we established vemurafenib-resistance melanoma cell strain together with acute vemurafenib treatment and characterized LINC01198 as the only one LncRNA up-regulated in both of stable vemurafenib-resistant and acute vemurafenib-treated melanoma cells. Functionally, loss of LINC01198 significantly compromised melanoma resistance against vemurafenib. Mechanistically, LINC01198 directly associates with TAOK1/2 to inhibit TAOK1/2 phosphorylation and thereby elicits Hippo signaling through TAOK/LATS axis, which redistributes YAP/TAZ into nucleus and promotes the expression and secretion of IL-1β to support vemurafenib resistance in melanoma. Our study not only identifies LINC01198 as a potent indicator and critical factor for driving vemurafenib resistance, but also suggests a series of therapeutic targets for tackling vemurafenib resistance in melanoma.

Figures