CUDC-907 reverses pathological phenotype of keloid fibroblasts in vitro and in vivo via dual inhibition of PI3K/Akt/mTOR signaling and HDAC2

摘要

Keloids are benign skin tumors with a high recurrence rate following surgical excision. Abnormal intracellular signaling is one of the key mechanisms involved in its pathogenesis. Over-activated phosphoinositide 3-kinase/RAC-alpha serine/threonine-protein kinase/mammalian target of rapamycin (PI3K/Akt/mTOR) signaling pathway and overproduction of histone deacetylases 2 (HDAC2) have also been observed in keloid fibroblasts (KFs). The present study aimed to explore the possibility of reversing the KF pathological phenotype using CUDC-907, a dual inhibitor of PI3K/Akt/mTOR pathway and HDACs. KFs and keloid xenografts were treated with CUDC-907 to examine its inhibitory effects on the pathological activities of KFs in vitro and in vivo. CUDC-907 inhibited cell proliferation, migration, invasion and extracellular matrix deposition of in vitro cultured KFs and also suppressed collagen accumulation and disrupted the capillaries of keloid explants ex vivo and in vivo. A mechanistic study of CUDC-907 revealed the initiation of cell cycle arrest at G2/M phase along with the enhanced expression of cyclin-dependent kinase inhibitor 1 and decreased expression of cyclin B in cells treated with CUDC-907. CUDC-907 not only inhibited AKT and mTOR phosphorylation and promoted the acetylation of histone H3, but also significantly inhibited the phosphorylation levels of Smad2/3 and Erk. These preclinical data demonstrating its anti-keloid effects suggest that CUDC-907 may represent a candidate drug for systemic keloid therapy.