1. Academic Validation
  2. Proto-oncogene Src links lipogenesis via lipin-1 to breast cancer malignancy

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

  • Nat Commun. 2020 Nov 17;11(1):5842. doi: 10.1038/s41467-020-19694-w.
Lintao Song 1 Zhihua Liu 2 Hui-Hui Hu 1 Ying Yang 1 Terytty Yang Li 1 Zhi-Zhong Lin 1 Jing Ye 3 Jianing Chen 4 Xi Huang 1 Dong-Tai Liu 1 Jing Zhou 1 Yiran Shi 1 Hao Zhao 1 Changchuan Xie 1 Lanfen Chen 1 Erwei Song 4 Shu-Yong Lin 1 Sheng-Cai Lin 5
Affiliations

Affiliations

  • 1 State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, 361102, Fujian, China.
  • 2 Center of Intestinal Barrier and Fecal Microbiota Transplantation, The Fifth Affiliated Hospital of Guangzhou Medical University, 510700, Guangdong, China.
  • 3 Department of Pathology, Xijing Hospital, Fourth Military Medical University, 710000, Shaanxi, China.
  • 4 Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, 510120, Guangzhou, China.
  • 5 State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, 361102, Fujian, China. [email protected].
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.

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