Bad to the bone: an RNA-sequencing study identifying a role for IKK-alpha in osteosarcoma cell division and progression

Osteosarcoma (OS) is the most prevalent primary malignant bone tumour generally made up of osteoblasts and is diagnosed in one to three individuals per million people every year. Despite research efforts, there has been little improvement to osteosarcoma treatment and prognosis in the last 30 years. Given these marginal improvements, research at a molecular level is imperative to enable discovery of therapeutic drug targets for osteosarcoma. Our present study utilises short-read RNA-sequencing techniques (Illumina) to a human OS cell line, U2OS with and without IKKα deletion by CRISPR-Cas9 knockdown. Our findings highlight that IKKα knockdown significantly decreases expression of cell division genes associated with OS progression, including AURKA, AURKB, TPX2, BIRC5, GTSE1, E2F2, FOXM1 and SPC24 (****p<0.0001). Interestingly, IKKα knockdown increased osteoclast-associated receptor (OSCAR) gene expression (****p<0.0001), which is a central receptor in bone degradation processes. Osteoclast activity is associated with decreased OS-derived metastasis, and hence this implies a role for IKKα in promoting metastasis. Additionally, with IL-1β (10 ng/mL) stimulation for 8 hours, we identified that there are several IL-1β-dependent, IKKα-mediated genes associated with OS tumour progression including CXCL5 and GAS7. Overall, IKKα appears to play a role in OS proliferation and progression and could be potentially pharmacologically targeted in OS.