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Fatty acid synthase is a primary target of MiR-15a and MiR-16-1 in breast cancer
Jingxuan Wang1,2, Xiao Zhang3, Jinming Shi3
1Department of Medical Oncology, the Third Affiliated Hospital of Harbin Medical University, Harbin P. R. China.
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.
Insights
MicroRNAs miR-15a and miR-16-1 suppress breast cancer growth by downregulating fatty acid synthase (FASN). These tumor suppressive microRNAs target FASN, a key factor in mammary oncogenesis and poor prognosis.
Area of Science:
- Molecular Biology
- Cancer Research
- Genetics
Background:
- Fatty acid synthase (FASN) is overexpressed in breast cancer, correlating with adverse patient outcomes.
- FASN plays a critical role in mammary tumor development and is a validated therapeutic target.
- MicroRNAs regulate gene expression post-transcriptionally by binding to target mRNA 3'-untranslated regions (3'-UTRs).
Purpose of the Study:
- To investigate the role of specific microRNA clusters, miR-15a-16-1 and miR-497-195, in regulating FASN expression in breast cancer.
- To determine the functional impact of miR-15a-16-1 and miR-497-195 on FASN levels and breast cancer cell proliferation.
Main Methods:
- Reporter assays were used to assess the inhibitory effect of microRNA clusters on a FASN 3'-UTR luciferase construct.
- Endogenous FASN levels and breast cancer cell proliferation were measured following ectopic expression of specific microRNAs.
- A sponge construct targeting the FASN 3'-UTR was employed to evaluate the necessity of microRNA binding for FASN regulation.
Main Results:
- Both miR-15a-16-1 and miR-497-195 clusters targeted the FASN 3'-UTR in reporter assays.
- Ectopic expression of miR-15a-16-1, but not miR-497-195, significantly reduced endogenous FASN levels and breast cancer cell proliferation.
- Restoring FASN expression partially rescued the proliferation defect induced by miR-15a-16-1.
Conclusions:
- miR-15a and miR-16-1 are key regulators that downregulate FASN expression in mammary cells.
- FASN is identified as a major target of the tumor-suppressive microRNAs miR-15a and miR-16-1.
- Targeting FASN by miR-15a-16-1 represents a significant mechanism underlying their anti-proliferative effects in breast cancer.
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