Tumor Necrosis Factor α-Induced Protein 8-Like Protein 1 Binds to Protein Arginine Methyltransferase 1 To Suppress the Methylation of Signal Transducer and Activator of Transcription 3 and Cell Growth in Oral Squamous Cell Carcinoma

Abstract

The tumor necrosis factor α-induced protein 8 (TIPE, also TNFAIP8 or OXi-α) family is a newly discovered series of proteins involved in immune regulation and tumorigenesis. TIPE1, a member of the TIPE/TNFAIP8/OXi-α family, has emerged as an anticancer-drug target, as it is promotes cancer cell apoptosis and inhibits cell proliferation. The current study aimed to systematically reveal that TIPE1 regulates the activity of protein arginine methyltransferase (PRMT)-1 and the subsequent methylation of signal transducer and activator of transcription (STAT)-3 to suppress oral squamous cell carcinoma (OSCC) growth. Results showed that TIPE1 was down-regulated in the OSCC cell lines (Tca8113, SCC25, Cal27, SCC15, and HSC27). TIPE1 overexpression significantly inhibited cell proliferation, colony formation, in vivo tumorgenicity, and Ki-67 expression in OSCC. TIPE1 was found to interact with the catalytic region of PRMT1 and inhibited STAT3 methylation. The effects of TIPE1 on OSCC cells were alleviated after PRMT1 overexpression, confirming the importance of this interaction to the tumor-suppressive effects of TIPE1. Together, those findings confirmed that TIPE1 mediated PRMT1 suppression through direct binding to its catalytic domain and then inhibited the methylation and expression of STAT3 in OSCC cells, thereby inhibiting cell growth and tumorgenicity.