FAT10 differentially stabilizes MYPT2 isoforms.

Myosin phosphatase (MP) is an enzyme complex that regulates muscle contraction and plays important roles in various physiological and pathological conditions. Myosin phosphatase targeting subunit (MYPT) 2, a subunit of MP, interacts with protein phosphatase 1c to regulate its phosphatase activity. MYPT2 exists in various isoforms that differ in the composition of essential motifs that contribute to its function. However, regulatory mechanisms underlying these isoforms are poorly understood. Human leukocyte antigen-F adjacent transcript 10 (FAT10) is a ubiquitin-like modifier that not only targets proteins for proteasomal degradation but also stabilizes its interacting proteins. In this study, we investigated the effect of the interaction between FAT10 and MYPT2 isoform a (the canonical full-length form of MYPT2) or MYPT2 isoform f (the natural truncated form of MYPT2). FAT10 interacted with both MYPT2 isoforms a and f; however, only MYPT2 isoform f was increased by FAT10, whereas MYPT2 isoform a remained unaffected by FAT10. We further confirmed that, in contrast to MYPT2 isoform a, MYPT2 isoform f undergoes rapid degradation via the ubiquitin-proteasome pathway and that FAT10 stabilizes MYPT2 isoform f by inhibiting its ubiquitination. Therefore, our findings suggest that the interaction between FAT10 and MYPT2 isoforms leads to distinct stabilization effects on each isoform, potentially modulating MP activity.

15-Prostaglandin Dehydrogenase Inhibition Enhances Colon Cancer Metastasis by Up-regulation of Epithelial-to-Mesenchymal Transition Genes.

BACKGROUND/AIM: Most deaths from colon cancer are due to metastasis. Recently, PGE2 was found to influence colon cancer invasion and metastasis. 15-PGDH, an enzyme that metabolizes PGE2, is known as a tumor suppressor in colonic carcinogenesis. This study investigated the effect of 15-PGDH on colon cancer metastasis. MATERIALS AND METHODS: 15-PGDH expression by immunohistochemical staining, clinicopathologic features, and 5-year cancer-specific survival were investigated in colon cancer patients. Liver metastasis was examined by assaying 15-PGDH activity in an animal model. Changes in PGE2, proliferation, migration, and invasion of the colorectal cancer cell line HCT116, were examined using a 15-PGDH inhibitor (SW033291) or enhancer (CDDO-ME). The expression of genes involved in the epithelial-to-mesenchymal transition (EMT) was also studied. RESULTS: The absence of 15-PGDH expression significantly correlated with advanced-stage, lymph node metastasis, and decreased cancer-specific survival in colon cancer patients. Inhibition of 15-PGDH increased colon cancer liver metastasis in the animal model. The 15-PGDH inhibitor, SW033291, increased PGE2 and decreased 15-PGDH expression on HCT116. However, treatment with CDDO-ME, a substance that enhances 15-PGDH, showed the opposite results. Inhibition of 15-PGDH increased cell proliferation, migration, and invasion, but activation of 15-PGDH showed the opposite effect. Inhibition of 15-PGDH also affected the EMT markers, N-cadherin, Snail, and Twist2. CONCLUSION: 15-PGDH inhibition increased colon cancer metastasis by inducing changes in EMT-related genes via an increase in PGE2 expression and could be a promising biomarker for anticancer treatment.