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
  • 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].
PMID: 33203880 DOI: 10.1038/s41467-020-19694-w
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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