Role and Molecular Mechanisms of N-Α-Acetyltransferase in Driving Tumor Invasion and Metastasis of Osteosarcoma(3/3)

Osteosarcoma, the most common malignant bone tumor, shows a potent capacity for local invasion and pulmonary metastasis. Aggressive metastasis is the main cause of the high mortality in osteosarcoma, yet the basis for its aggressive behavior remains elusive. Human N-α-acetyltransferase 10 protein (hNaa10p; also known as human arrest-defective 1), the catalytic subunit of the N-acetyltransferase A complex, catalyzes both N-α-acetylation and ε-acetylation and thereby may affect protein function stability. Studies have reported conflicting results regarding the role of Naa10p in the tumorigenesis or tumor metastasis of several cancer types; however, the modulatory effects of Naa10p on the invasion and metastasis of osteosarcoma and the underlying mechanisms of these effects have not yet been studied. Preliminary studies have found high Naa10p expression in highly invasive osteosarcoma cell lines (HOS, 143B, and U2OS), but low Naa10p expression in poorly invasive osteosarcoma cell lines (MG-63 and Saos-2). Clinical samples have indicated higher expression of Naa10p in osteosarcoma tissues compared with normal bone tissues. Naa10p depletion caused by shRNA suppressed migratory and invasive capabilities in highly invasive osteosarcoma cell lines, whereas Naa10p overexpression promoted tumor migration/invasion in poorly invasive osteosarcoma cell lines. According to our preliminary data, we hypothesize that Naa10p is critical for regulating multiple genes that are involved in osteosarcoma metastasis. Furthermore, protease array data indicate that the expression of an extracellular matrix-degrading enzyme, matrix metalloproteinase-2 (MMP-2), was downregulated significantly in Naa10p-depleted osteosarcoma cells, indicating that MMP-2 might be an important downstream target of Naa10p. Further evidence shows that Naa10p depletion-mediated MMP-2 protein downregulation is partially attributed to reduced mRNA levels and protein instability, indicating that the underlying mechanism of the MMP-2 protein decrease might be a transcriptional, posttranscriptional, or posttranslational process. This project will use in vitro and in vivo models to explore the molecular mechanisms underlying Naa10p-regulated MMP-2 expression and the role of the Naa10p-MMP-2 axis in cancer cell invasion and metastasis. This study will also analyzethe clinical correlation between Naa10p and MMP-2 in tumor specimens from osteosarcoma patients and further investigate the clinical significance of the Naa10p-MMP-2 axis in cancer metastasis.