Epigenetic Control of Cancer Cell Proliferation and Cell Cycle Progression by HNRNPK via Promoting Exon 4 Inclusion of Histone Code Reader SPIN1

Heterogeneous nuclear ribonucleoprotein K (HNRNPK, hnRNP K), a multifunctional RNA/DNA binding protein, mainly regulates transcription, translation and RNA splicing, and then plays oncogenic roles in many cancers. However, the related mechanisms remain largely unknown. Here, we found that HNRNPK can partially epigenetically regulate cancer cell proliferation via increasing transcription and exon 4-inclusion of SPIN1, an important oncogenic histone code reader. This exon 4 skipping event of SPIN1 generates a long non-coding RNA, followed by the downregulation of SPIN1 protein. SPIN1 is one of the most significantly co-expressed genes of HNRNPK in thirteen TCGA cancers. Our further studies revealed HNRNPK knockdown significantly inhibited cell growth and cell cycle progression in oral squamous cell carcinoma (OSCC) cells and promoted cell apoptosis. Overexpression of SPIN1 was able to partially rescue the growth inhibition triggered by HNRNPK knockdown. Moreover, CCND1 (Cyclin D1), a key cell cycle regulator and oncogene, epigenetically up-regulated by SPIN1, was also positively regulated by HNRNPK. In addition, we discovered that HNRNPK promoted SPIN1 exon 4 inclusion by interacting with an intronic splicing enhancer in intron 4. Collectively, our study suggests a novel epigenetic regulatory pathway of HNRNPK in OSCC, mediated by controlling the transcription activity and alternative splicing of SPIN1 gene.