Fatty acid synthase is a primary target of MiR-15a and MiR-16-1 in breast cancer.

Jingxuan Wang,Jianfeng Xu,Wennuan Liu,Guangchao Sui,Meimei Wan,Qiang Zhang,Qingyuan Zhang,Xiao Zhang,Yunxuan Wang,Paul Cao,Steven J Kridel,Jinming Shi

doi:10.18632/oncotarget.12479

Abstract

Fatty acid synthase (FASN) is upregulated in breast cancer and correlates with poor prognosis. FASN contributes to mammary oncogenesis and serves as a bona fide target in cancer therapies. MicroRNAs inhibit gene expression through blocking mRNA translation or promoting mRNA degradation by targeting their 3′-UTRs. We identified four microRNAs in two microRNA clusters miR-15a-16-1 and miR-497-195 that share a common seed sequence to target the 3′-UTR of the FASN mRNA. In reporter assays, both of these microRNA clusters inhibited the expression of a reporter construct containing the FASN 3′-UTR. However, only ectopic miR-15a-16-1, but not miR-497-195, markedly reduced the levels of endogenous FASN in breast cancer cells. Both miR-15a and miR-16-1 contributes to inhibiting FASN expression and breast cancer cell proliferation. Consistently, a sponge construct consisting of eight repeats of the FASN 3′-UTR region targeted by these microRNAs could markedly increase endogenous FASN levels in mammary cells. When FASN expression was restored by ectopic expression in breast cancer cells, retarded cell proliferation caused by miR-15a-16-1 was partially rescued. In conclusion, we demonstrated that FASN expression is primarily downregulated by miR-15a and miR-16-1 in mammary cells and FASN is one of the major targets of these two tumor suppressive microRNAs.

Highlights

In mammalian cells, fatty acid synthase (FASN) is the central lipogenic enzyme promoting the de novo synthesis of long-chain fatty acids from acetyl-CoA and malonyl-CoA [1]
Among the miRNA candidates identified by this algorithm, we found that miR-15a, -16-1, -497 and -195 have their seed sequence reverse-complementarily match a 7-nt stretch (5′-UGCUGCU-3′) on the 3′-UTR of the Fatty acid synthase (FASN) mRNA
Deregulated gene expression contributes to mammary oncogenesis

Summary

Introduction

Fatty acid synthase (FASN) is the central lipogenic enzyme promoting the de novo synthesis of long-chain fatty acids from acetyl-CoA and malonyl-CoA [1]. Inhibition of FASN activity leads to cytotoxic effects, including cell growth arrest and apoptosis [7, 8]. Overexpressed FASN promotes HER2-regulated signaling and leads to enhanced cell proliferation [9, 10]. Recent studies indicated that FASN plays an important role in regulating expression of genes involved in apoptosis and DNA repair [11]. Inhibiting FASN expression or its activity represents a promising approach of therapeutic treatment for multiple cancers, including breast cancer [2]

Methods

Results

Conclusion