Tumor Promoting Role of NRIP1 in Oral Squamous Cell Carcinoma: The Involvement of NSD2-Mediated Histone Methylation of DGCR8.

Oral squamous cell carcinoma (OSCC) remains the most prevalent malignance in the head and neck with highly aggressive attributes. This study investigates the functions of nuclear receptor interacting protein 1 (NRIP1) and its target transcripts in the progression of OSCC. By analyzing four OSCC-related Gene Expression Omnibus (GEO) datasets (GSE9844, GSE23558, GSE25104 and GSE74530) and querying bioinformatics systems, we obtained NRIP1 as an aberrantly highly expressed transcription factor in OSCC. Increased NRIP1 was detected in OSCC cell lines. Artificial downregulation of NRIP1 significantly suppressed proliferation, migration and invasion, resistance to apoptosis, tumorigenicity, and in vivo metastatic potential of OSCC cells. Moreover, the bioinformatics analyses suggested nuclear receptor binding SET domain protein 2 (NSD2) as a target of NRIP1 and DGCR8 microprocessor complex subunit (DGCR8) as a target of NSD2. Indeed, we validated by chromatin immunoprecipitation and luciferase assays that NRIP1 activated the transcription of NSD2, and NSD2 increased DGCR8 transcription by modulating histone methylation near the DGCR8 promoter. Either NSD2 or DGCR8 upregulation in OSCC cells rescued their malignant properties. Collectively, this study demonstrates that NRIP1 augments malignant properties of OSCC cells by activating NSD2-mediated histone methylation of DGCR8.