2. Academic Validation
  3. Blockade of a novel MAP4K4-LATS2-SASH1-YAP1 cascade inhibits tumorigenesis and metastasis in luminal breast cancer

Blockade of a novel MAP4K4-LATS2-SASH1-YAP1 cascade inhibits tumorigenesis and metastasis in luminal breast cancer

  • J Biol Chem. 2024 Apr 22:107309. doi: 10.1016/j.jbc.2024.107309.
Pingping Yang 1,  Yadong Li 2,  Jing Hou 3,  Daoqiu Wu 4,  Xing Zeng 5,  Zhen Zeng 6,  Jing Zhang 2,  Yu Xiong 6,  Lian Chen 2,  Dan Yang 2,  Xin Wan 2,  Zhixiong Wu 2,  Lei Jia 2,  Qianfan Liu 2,  Qingxiang Lu 4,  Xue Zou 2,  Wen Fang 4,  Xiaohua Zeng 7,  Ding'an Zhou 8
Affiliations

Affiliations

  • 1 Clinical Research Center, the Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, 550004, P. R. China; School of Clinical Laboratory Science, Guizhou Medical University, Guiyang, Guizhou, 550004, P. R. China; Department of Laboratory Medicine, People's Hospital of Qiannan Prefecture, Guizhou, China, 558000, P. R. China.
  • 2 Clinical Research Center, the Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, 550004, P. R. China.
  • 3 Breast Cancer Surgery Department, Guizhou Provincial People's Hospital. Guiyang, Guizhou, 550001, P. R. China.
  • 4 School of Clinical Laboratory Science, Guizhou Medical University, Guiyang, Guizhou, 550004, P. R. China.
  • 5 The Fifth Clinical College, Chongqing Medical University, Chongqing, 400010, China.
  • 6 Clinical Research Center, the Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, 550004, P. R. China; School of Clinical Laboratory Science, Guizhou Medical University, Guiyang, Guizhou, 550004, P. R. China.
  • 7 Chongqing University Cancer Hospital & Chongqing Cancer Institute & Chongqing Cancer Hospital, Chongqing, 400030, P. R. China. Electronic address: zxiaohuacqu@126.com.
  • 8 Clinical Research Center, the Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, 550004, P. R. China; Key Laboratory of Endemic and Ethnic Diseases, Ministry of Education & Key Laboratory of Medical Molecular Biology of Guizhou Province, Guizhou Medical University, Guiyang, Guizhou, China. Electronic address: gmuzhouda@gmc.edu.cn.
PMID: 38657867 DOI: 10.1016/j.jbc.2024.107309
Abstract

Novel components in the noncanonical Hippo pathway that mediate the growth, metastasis, and drug resistance of breast Cancer (BC) cells need to be identified. Here, we showed that SAM and SH3 domain containing protein 1 (SASH1) expression is negatively correlated with mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4) expression in a subpopulation of patients with luminal-subtype BC. Downregulated SASH1 and upregulated MAP4K4 synergistically regulated the proliferation, migration, and invasion of luminal-subtype BC cells. The expression of LATS2, SASH1 and YAP1 and the phosphorylation of YAP1 were negatively regulated by MAP4K4, and LATS2 then phosphorylated SASH1 to form a novel MAP4K4-LATS2-SASH1-YAP1 cascade. Dephosphorylation of Yes1 associated transcriptional regulator (YAP1), YAP1/TAZ nuclear translocation and downstream transcriptional regulation of YAP1 were promoted by the combined effects of ectopic MAP4K4 expression and SASH1 silencing. Targeted inhibition of MAP4K4 blocked proliferation, cell migration and ER signaling both in vitro and in vivo. Our findings reveal a novel MAP4K4-LATS2-SASH1-YAP1 phosphorylation cascade, a noncanonical Hippo pathway that mediates ER signaling, tumorigenesis and metastasis in breast Cancer. Targeted intervention with this noncanonical Hippo pathway may constitute a novel alternative therapeutic approach for endocrine-resistant BC.

Keywords

Luminal-subtype breast cancers; Noncanonical Hippo pathway; Pharmacological MAP4K4 inhibition; Tumorigenesis.

Figures
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  • HY-100343
    99.40%, MAP4K4抑制剂
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