Hyaluronan-Induced CD44-iASPP Interaction Affects Fibroblast Migration and Survival

SIMPLE SUMMARY: The hyaluronan receptor CD44 plays a vital role in tumor cell growth and chemotherapy resistance. The tumor suppressor p53 binds to the CD44 promoter via a non-canonical p53 consensus sequence and suppresses CD44 expression, promoting apoptosis. Conversely, the apoptotic function of p53 is negatively regulated through its interactions with iASPP, a specific inhibitor of p53-induced apoptosis in both normal and cancer cells. CD44, p53, and iASPP are co-expressed in a wide array of human cancers; however, the precise role of CD44 in p53-mediated apoptosis is not known. We discovered that the standard isoform of CD44 physically bound to iASPP and dictated the sub-cellular localization of iASPP-p53 complexes. The iASPP-CD44 complex affected fibroblast adhesion, migration, growth, and p53-mediated apoptosis. ABSTRACT: In the present study, we show that the inhibitor of the apoptosis-stimulating protein of p53 (iASPP) physically interacts with the hyaluronan receptor CD44 in normal and transformed cells. We noticed that the CD44 standard isoform (CD44s), but not the variant isoform (CD44v), bound to iASPP via the ankyrin-binding domain in CD44s. The formation of iASPP-CD44s complexes was promoted by hyaluronan stimulation in fibroblasts but not in epithelial cells. The cellular level of p53 affected the amount of the iASPP-CD44 complex. iASPP was required for hyaluronan-induced CD44-dependent migration and adhesion of fibroblasts. Of note, CD44 altered the sub-cellular localization of the iASPP-p53 complex; thus, ablation of CD44 promoted translocation of iASPP from the nucleus to the cytoplasm, resulting in increased formation of a cytoplasmic iASPP-p53 complex in fibroblasts. Overexpression of iASPP decreased, but CD44 increased the level of intracellular reactive oxygen species (ROS). Knock-down of CD44s, in the presence of p53, led to increased cell growth and cell density of fibroblasts by suppression of p27 and p53. Our observations suggest that the balance of iASPP-CD44 and iASPP-p53 complexes affect the survival and migration of fibroblasts.