Suppressing migration and invasion of H1299 lung cancer cells by honokiol through disrupting expression of an HDAC6-mediated matrix metalloproteinase 9

Abstract

Metastasis is the crucial mechanism to cause high mortality in lung cancer. Degradation of extracellular matrix (ECM) by proteolytic enzymes, especially matrix metalloproteinases (MMPs), is a key process for promoting cancer cell migration and invasion. Therefore, targeting MMPs might be a strategy for lung cancer metastasis suppression. Honokiol, a biological active component of Magnolia officinalis, has been indicated to suppress lung cancer tumorigenesis through epigenetic regulation. However, the regulation of MMPs-mediated migration and invasion by honokiol through epigenetic regulation in lung cancer is still a mystery. In the present study, the migration and invasion ability of H1299 lung cancer was suppressed by noncytotoxic concentrations of honokiol treatment. The proteolytic activity of MMP-9, rather than MMP-2, was inhibited in honokiol-treated H1299 cells. Honokiol-inhibited MMP-9 expression was through promoting MMP-9 protein degradation rather than suppressing transcription mechanism. Furthermore, the expression of specific histone deacetylases 6 (HDAC6) substrate, acetyl-α-tubulin, was accumulated after honokiol incubation. The disassociation of MMP-9 with hyper-acetylated heat shock protein 90 (Hsp90) was observed resulting in MMP-9 degradation after honokiol treatment. Meanwhile, honokiol-suppressed MMP-9 expression and invasion ability of H1299 lung cancer cells was rescued by HDAC6 overexpression. Accordingly, the results suggested that the suppression of migration and invasion activities by honokiol was through inhibiting HDAC6-mediated Hsp90/MMP-9 interaction and followed by MMP-9 degradation in lung cancer.