Converting the tumor suppressor function of WWOX to tumor promoting by Serine 14 phosphorylation

Abstract

Accumulation of tumor suppressor WWOX with Ser14 phosphorylation has been shown in growing solid tumors and brain lesions with Alzheimer's disease. Functional significance of this regard is unknown. A portion of cytosolic WWOX is recruited to the cell membrane/cytoskeleton by binding hyaluronidase Hyal‐2. Here, we identified a cell surface‐exposed N‐terminal epitope WWOX7‐21 (amino acid #7 to 21), which is in front of the first WW domain. Treatment of breast 4T1 cancer stem cell spheres with the WWOX7‐21 antibody resulted in dramatic inhibition of ceritinib‐mediated cell death (>85% inhibition). Similar results were observed using other therapeutic chemicals. In contrast, when 4T1 stem cell spheres were treated with micromolar levels of synthetic WWOX7‐21 and WWOX7‐11 peptides, 4T1 cells in the spheres became highly susceptible to death by ceritinib. Notably, when pS14‐WWOX7‐11 peptide was used to treat the 4T1 spheres, cells significantly acquired resistance to ceritinib. WWOX7‐21 and WWOX7‐11 peptides caused spleen Z cell expansion and activation by expressing Hyal‐2, Zfra, and Noxa to block 4T1 growth and metastasis in mice. Accordingly, stimulating membrane Hyal‐2 with agonist Hyal‐2 antibody, sonicated hyaluronan and Zfra peptide primed Z cells for activation and blocking cancer growth in vivo. Purified activated Z cells aggressively attacked and caused death of 4T1 stem cells in spheres in vitro, as determined by time‐lapse microscopy. In stark contrast, pSer14‐WWOX7‐21 peptide significantly induced clonal expansion of spleen CD8alpha+ T and CD19+ B cells in vivo and enhanced cancer growth. Together, phosphorylation at Ser14 turns WWOX from tumor suppressor into tumor promoter.Support or Funding InformationMOST, TaiwanThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.