Hyaluronan activates Hyal-2/WWOX/Smad4 signaling and causes bubbling cell death when the signaling complex is overexpressed

Li Jin Hsu, Qunying Hong, Shur Tzu Chen, Hsiang Lin Kuo, Lori Schultz, John Heath, Sing Ru Lin, Ming Hui Lee, Dong Zhang Li, Zih Ling Li, Hui Ching Cheng, Gerard Armand, Nan Shan Chang

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Malignant cancer cells frequently secrete significant amounts of transforming growth factor beta (TGF-β), hyaluronan (HA) and hyaluronidases to facilitate metastasizing to target organs. In a non-canonical signaling, TGF-β binds membrane hyaluronidase Hyal-2 for recruiting tumor suppressors WWOX and Smad4, and the resulting Hyal-2/WWOX/Smad4 complex is accumulated in the nucleus to enhance SMAD-promoter dependent transcriptional activity. Yeast two-hybrid analysis showed that WWOX acts as a bridge to bind both Hyal-2 and Smad4. When WWOX-expressing cells were stimulated with high molecular weight HA, an increased formation of endogenous Hyal-2/WWOX/Smad4 complex occurred rapidly, followed by relocating to the nuclei in 20-40 min. In WWOX-deficient cells, HA failed to induce Smad2/3/4 relocation to the nucleus. To prove the signaling event, we designed a real time tri-molecular FRET analysis and revealed that HA induces the signaling pathway from ectopic Smad4 to WWOX and finally to p53, as well as from Smad4 to Hyal-2 and then to WWOX. An increased binding of the Smad4/Hyal-2/WWOX complex occurs with time in the nucleus that leads to bubbling cell death. In contrast, HA increases the binding of Smad4/WWOX/p53, which causes membrane blebbing but without cell death. In traumatic brain injury-induced neuronal death, the Hyal-2/WWOX complex was accumulated in the apoptotic nuclei of neurons in the rat brains in 24 hr post injury, as determined by immunoelectron microscopy. Together, HA activates the Hyal-2/WWOX/Smad4 signaling and causes bubbling cell death when the signaling complex is overexpressed.

Original languageEnglish
Pages (from-to)19137-19155
Number of pages19
JournalOncotarget
Volume8
Issue number12
DOIs
Publication statusPublished - 2017

All Science Journal Classification (ASJC) codes

  • Oncology

Fingerprint Dive into the research topics of 'Hyaluronan activates Hyal-2/WWOX/Smad4 signaling and causes bubbling cell death when the signaling complex is overexpressed'. Together they form a unique fingerprint.

  • Cite this

    Hsu, L. J., Hong, Q., Chen, S. T., Kuo, H. L., Schultz, L., Heath, J., Lin, S. R., Lee, M. H., Li, D. Z., Li, Z. L., Cheng, H. C., Armand, G., & Chang, N. S. (2017). Hyaluronan activates Hyal-2/WWOX/Smad4 signaling and causes bubbling cell death when the signaling complex is overexpressed. Oncotarget, 8(12), 19137-19155. https://doi.org/10.18632/oncotarget.13268