EGFR modulates monounsaturated fatty acid synthesis through phosphorylation of SCD1 in lung cancer

Jiqin Zhang,Xiuqi Wu,Hai Wang,Huamao Wang,Biao Wang,Min Zhou,Mi Tian,Fei Song,Xiaorong Pan,Zonghai Li,Yuanhui Jia,Xiaojing Zhao,Bizhi Shi,Hua Jiang

doi:10.1186/s12943-017-0704-x

Abstract

BackgroundEpidermal growth factor receptor (EGFR), a well-known oncogenic driver, contributes to the initiation and progression of a wide range of cancer types. Aberrant lipid metabolism including highly produced monounsaturated fatty acids (MUFA) is recognized as a hallmark of cancer. However, how EGFR regulates MUFA synthesis in cancer remains elusive. This is the focus of our study.MethodsThe interaction between EGFR and stearoyl-CoA desaturase-1 (SCD1) was detected byco-immunoprecipitation. SCD1 protein expression, stability and phosphorylation were tested by western blot. The synthesis of MUFA was determined by liquid chromatography-mass spectrometry. The growth of lung cancer was detected by CCK-8 assay, Annexin V/PI staining, colony formation assay and subcutaneous xenograft assay. The expression of activated EGFR, phosphorylated and total SCD1 was tested by immunohistochemistry in 90 non-small cell lung cancersamples. The clinical correlations were analyzed by Chi-square test, Kaplan-Meier survival curve analysis and Cox regression.ResultsEGFR binds to and phosphorylates SCD1 at Y55. Phosphorylation of Y55 is required for maintaining SCD1 protein stability and thus increases MUFA level to facilitate lung cancer growth. Moreover, EGFR-stimulated cancer growth depends on SCD1 activity. Evaluation of non-small cell lung cancersamples reveals a positive correlation among EGFR activation, SCD1 Y55 phosphorylation and SCD1 protein expression. Furthermore, phospho-SCD1 Y55 can serve as an independent prognostic factor for poor patient survival.ConclusionsOurstudy demonstrates that EGFR stabilizes SCD1 through Y55 phosphorylation, thereby up-regulating MUFA synthesis to promote lung cancer growth. Thus, we provide the first evidence that SCD1 can be subtly controlled by tyrosine phosphorylation and uncover a previously unknown direct linkage between oncogenic receptor tyrosine kinase and lipid metabolism in lung cancer. We also propose SCD1 Y55 phosphorylation as a potential diagnostic marker for lung cancer.

Highlights

Epidermal growth factor receptor (EGFR), a well-known oncogenic driver, contributes to the initiation and progression of a wide range of cancer types
EGFR interacts with stearoyl-CoA desaturase-1 (SCD1) Given that EGFR can act as anoncogenic driver and phosphorylate a variety of cancer-promoting factors, we speculated whether it is capable of directly regulating the key enzymes involved in lipid metabolism
Co-immunoprecipitation assay in 293 T cells showed that there was a protein-protein interaction between EGFR and SCD1 (Fig. 1a and b)

Summary

Introduction

Epidermal growth factor receptor (EGFR), a well-known oncogenic driver, contributes to the initiation and progression of a wide range of cancer types. Aberrant lipid metabolism including highly produced monounsaturated fatty acids (MUFA) is recognized as a hallmark of cancer. How EGFR regulates MUFA synthesis in cancer remains elusive. An increasing number of studies suggest that altered lipid metabolism is one of new hallmarks of cancer in recent years [1, 2]. Recent studies disclose that high level of SCD1 protein expression is correlated with poor patient prognosis in breast cancer and hepatocellular carcinoma [18, 19]. It has been reported that sterol response element-binding protein (SREBP), peroxisome proliferator-activated receptor (PPAR), LXR, NF-1 and AP-2 modulate the gene transcription of SCD1 [20,21,22]. How SCD1 is affected by other post-translational mechanisms has been poorly studied up to now

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