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

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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-017-0704-x) contains supplementary material, which is available to authorized users.

Emerging functions of the EGFR in cancer

“…Furthermore, the EGFR has been recently found to directly phosphorylate and, thereby, stabilize stearoyl‐CoA desaturase‐1 (SCD1), resulting in the upregulation of monounsaturated fatty acid production (Zhang et al ., ). Notably, phosphorylation of SDC1 correlates with poor prognosis of glioblastoma multiforme (Zhang et al ., ), suggesting that it might have a causative role in these tumors.…”

“…In this context, EGFR signaling has been involved in the regulation of several metabolic processes that are critical for cancer cell proliferation: from the biosynthesis of fatty acids and pyrimidines, to glucose catabolism (Guo et al ., ; Makinoshima et al ., ). The EGFR promotes these metabolic pathways both directly by phosphorylating rate‐limiting enzymes (Lim et al ., ; Zhang et al ., ), or indirectly through activation of the MYC transcription factor and of the AKT signaling cascade (Babic et al ., ; Guo et al ., ; Makinoshima et al ., , , and reviewed in DeBerardinis and Chandel, ; Masui et al ., ).…”

Metabolic Remodelling: An Accomplice for New Therapeutic Strategies to Fight Lung Cancer

“…Hexokinase 2 (HK-2) is the first rate-limiting enzyme in the glycolytic pathway and overexpression of HK-2 has wildly been observed in cancer cells, correlating with poor overall survival in cancer patients [35][36][37]. Mutant EGFR (epidermal growth factor receptor 1) promotes metabolic remodelling in non-small-cell lung carcinoma (NSCLC) with increased aerobic glycolysis and PPP (pentose phosphate pathway), altered pyrimidine biosynthesis and upregulation of monounsaturated fatty acids [38][39][40]. KRAS (Kirsten rat sarcoma viral oncogene homolog GTPase)-mutated NSCLC cells express higher levels of enzymes involved in glycolysis, such as pyruvate kinase isozyme M2 (PKM2) and lactate dehydrogenase A (LDHA) compared with nonmalignant cells, indicating alterations in glucose metabolism and PPP (glicose-6-fosfato dehydrogenase (G6PD), transketolase (TKT) and 6-phosphogluconate dehydrogenase (6PGD)) [41].…”

“…These facts indicate the need of glutamine as a source for bioenergetics and biosynthesis in EGFR-mutated NSCLCs, as glucose is mainly used to sustain PPP and consequently cancer cells proliferation. Another study, showed the role of EGFR in the stabilization by phosphorylation of stearoyl-CoA desaturase-1 (SCD1), augmenting monounsaturated fatty acid synthesis and sustaining cell proliferation [40]. In addition, phosphorylated SCD1 levels were reported as an independent prognostic factor for poor survival in NSCLC [40].…”

Epidermal growth factor receptor inhibitor AG1478 affects HepG2 cell proliferation, cell cycle, apoptosis and c-Myc protein expression in a dose-dependent manner

“…This process changes cell cycle-related genes, induces cancer cell proliferation and suppresses apoptosis [10,11]. The levels of EGFR in normal tissues were very low, while EGFR was highly expressed in many tumour tissues [12,13]. In our previous study [14], immunohistochemistry was used to detect the expression of EGFR in hepatocellular carcinoma and adjacent tissues.…”