Proto-oncogene Src links lipogenesis via lipin-1 to breast cancer malignancy

Lintao Song, Zhihua Liu, Hui-Hui Hu, Ying Yang, Terytty Yang Li, Zhi-Zhong Lin, Jing Ye, Jianing Chen, Xi Huang, Dong-Tai Liu, Jing Zhou, Yiran Shi, Hao Zhao, Changchuan Xie, Lanfen Chen, Erwei Song, Shu-Yong Lin and Sheng-Cai Lin ()
Additional contact information
Lintao Song: Xiamen University
Zhihua Liu: The Fifth Affiliated Hospital of Guangzhou Medical University
Hui-Hui Hu: Xiamen University
Ying Yang: Xiamen University
Terytty Yang Li: Xiamen University
Zhi-Zhong Lin: Xiamen University
Jing Ye: Fourth Military Medical University
Jianing Chen: Sun Yat-Sen University
Xi Huang: Xiamen University
Dong-Tai Liu: Xiamen University
Jing Zhou: Xiamen University
Yiran Shi: Xiamen University
Hao Zhao: Xiamen University
Changchuan Xie: Xiamen University
Lanfen Chen: Xiamen University
Erwei Song: Sun Yat-Sen University
Shu-Yong Lin: Xiamen University
Sheng-Cai Lin: Xiamen University

Nature Communications, 2020, vol. 11, issue 1, 1-13

Abstract: Abstract Increased lipogenesis has been linked to an increased cancer risk and poor prognosis; however, the underlying mechanisms remain obscure. Here we show that phosphatidic acid phosphatase (PAP) lipin-1, which generates diglyceride precursors necessary for the synthesis of glycerolipids, interacts with and is a direct substrate of the Src proto-oncogenic tyrosine kinase. Obesity-associated microenvironmental factors and other Src-activating growth factors, including the epidermal growth factor, activate Src and promote Src-mediated lipin-1 phosphorylation on Tyr398, Tyr413 and Tyr795 residues. The tyrosine phosphorylation of lipin-1 markedly increases its PAP activity, accelerating the synthesis of glycerophospholipids and triglyceride. Alteration of the three tyrosine residues to phenylalanine (3YF-lipin-1) disables lipin-1 from mediating Src-enhanced glycerolipid synthesis, cell proliferation and xenograft growth. Re-expression of 3YF-lipin-1 in PyVT;Lpin1−/− mice fails to promote progression and metastasis of mammary tumours. Human breast tumours exhibit increased p-Tyr-lipin-1 levels compared to the adjacent tissues. Importantly, statistical analyses show that levels of p-Tyr-lipin-1 correlate with tumour sizes, lymph node metastasis, time to recurrence and survival of the patients. These results illustrate a direct lipogenesis-promoting role of the pro-oncogenic Src, providing a mechanistic link between obesity-associated mitogenic signaling and breast cancer malignancy.

Date: 2020
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DOI: 10.1038/s41467-020-19694-w

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