The HNF4a-BC200-FMR1-Positive Feedback Loop Promotes Growth and Metastasis in Invasive Mucinous Lung Adenocarcinoma

Abstract

Invasive mucinous lung adenocarcinoma (IMA) is a subtype of lung adenocarcinoma with a strong invasive ability. IMA frequently carries "undruggable" KRAS mutations, highlighting the need for new molecular targets and therapies. Nuclear receptor HNF4a is abnormally enriched in IMA, but the potential of HNF4a to be a therapeutic target for IMA remains unknown. Here, we report that P2 promoter-driven HNF4a expression promotes IMA growth and metastasis. Mechanistically, HNF4a transactivated lncRNA BC200, which acted as a scaffold for mRNA binding protein FMR1. BC200 promoted the ability of FMR1 to bind and regulate stability of cancer-related mRNAs and HNF4a mRNA, forming a positive feedback circuit. Mycophenolic acid, the active metabolite of FDA-approved drug mycophenolate mofetil, was identified as an HNF4a antagonist exhibiting anti-IMA activities in vitro and in vivo. This study reveals the role of a HNF4a-BC200-FMR1- positive feedback loop in promoting mRNA stability during IMA progression and metastasis, providing a targeted therapeutic strategy for IMA. Significance: Growth and metastatic progression of invasive mucinous lung adenocarcinoma can be restricted by targeting HNF4a, a critical regulator of a BC200-FMR1-mRNA stability axis. _2021 American Association for Cancer Research.