Hippo signaling suppresses tumor cell metastasis via a Yki-Src42A positive feedback loop

  • Cell Death Dis. 2021 Dec 3;12(12):1126. doi: 10.1038/s41419-021-04423-y.
Yan Ding   #  1 ,  Guiping Wang   #  2 ,  Meixiao Zhan   #  3 ,  Xiaohan Sun   #  1 ,  Yanran Deng  4 ,  Yunhe Zhao  1 ,  Bin Liu  1 ,  Qingxin Liu  5 ,  Shian Wu  6 ,  Zizhang Zhou  7
Affiliations
  • 1. State Key Laboratory of Crop Biology, College of Life Sciences, Shandong Agricultural University, 271018, Tai'an, China.
  • 2. Tianjin Key Laboratory of Protein Sciences, State Key Laboratory of Medical Chemical Biology, College of Life Sciences, Nankai University, 300071, Tianjin, China.
  • 3. Center of Intervention radiology, Zhuhai Precision Medicine Center, Zhuhai People's Hospital, 519000, Zhuhai, China.
  • 4. Jiangsu Key laboratory of Drug Screening, China Pharmaceutical University, 210009, Nanjing, China.
  • 5. State Key Laboratory of Crop Biology, College of Life Sciences, Shandong Agricultural University, 271018, Tai'an, China. [email protected].
  • 6. Tianjin Key Laboratory of Protein Sciences, State Key Laboratory of Medical Chemical Biology, College of Life Sciences, Nankai University, 300071, Tianjin, China. [email protected].
  • 7. State Key Laboratory of Crop Biology, College of Life Sciences, Shandong Agricultural University, 271018, Tai'an, China. [email protected].
  • # Contributed equally.
PMID: 34862372 DOI: 10.1038/s41419-021-04423-y
Abstract

Metastasis is an important cause of death from malignant tumors. It is of great significance to explore the molecular mechanism of metastasis for the development of anti-cancer drugs. Here, we find that the Hippo pathway hampers tumor cell metastasis in vivo. Silence of hpo or its downstream wts promotes tumor cell migration in a Yki-dependent manner. Furthermore, we identify that inhibition of the Hippo pathway promotes tumor cell migration through transcriptional activating src42A, a Drosophila homolog of the Src oncogene. Yki activates src42A transcription through direct binding its intron region. Intriguingly, Src42A further increases Yki transcriptional activity to form a positive feedback loop. Finally, we show that Src is also a target of YAP and important for YAP to promote the migration of human hepatocellular carcinoma cells. Together, our findings uncover a conserved Yki/YAP-Src42A/Src positive feedback loop promoting tumor cell migration and provide Src as a potential therapeutic target for YAP-driven metastatic tumors.

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