Regnase-1 Promotes Tumor-Initiating Activity in Non-Small Cell Lung Cancer

Regnase-1, encoded by the ZC3H12A gene, is a well-known RNase that suppresses inflammation by degrading the mRNAs of inflammatory cytokines. However, its role in cancer pathogenesis, especially in non-small cell lung cancer (NSCLC), remains poorly understood. Through an analysis of public databases, we found that NSCLC patients with higher ZC3H12A expression levels had a worse prognosis than those with lower levels. To explore the function of Regnase-1 in NSCLC, we knocked out the ZC3H12A gene in NSCLC cell lines and compared their transcriptomes with those of parental cells. This analysis identified the SOX2 pathway as a common pathway suppressed by Regnase-1 deficiency. Consistent with the SOX2 contribution to the cancer stemness, Regnase-1 inhibition impaired oncosphere growth and tumor formation of cell lines derived from adenocarcinoma, squamous cell carcinoma and large cell carcinoma. It was also effective for NRF2-activated NSCLC cells, which are highly resistant to most of the therapeutics. Notably, post-tumorigenic suppression of Regnase-1 significantly inhibited tumor growth, suggesting that Regnase-1 could be a promising therapeutic target for post-tumorigenic treatment of NSCLC. Given recent studies describing that Regnase-1 inhibition enhances anti-cancer immunity, we propose that targeting Regnase-1 could be an ideal strategy for controlling intractable cancers by both suppressing cancer cells and activating anti-cancer immunity.