m⁵ C and m⁶ A modification of long noncoding NKILA accelerates cholangiocarcinoma progression via the miR-582-3p-YAP1...

Cholangiocarcinoma (CCA) is a severe malignancy originating from the bile duct and the second most common primary liver cancer. NF-kappa B interacting lncRNA (NKILA) is a functional lncRNA, which play important role in human cancers. However, the role and underlying mechanism of NKILA in CCA remains largely unknown. Here, our study demonstrated that NKILA was significantly upregulated in CCA tissues and cells. Overexpression of NKILA is associated with advanced TNM stage, lymph node and distant metastasis, and also indicated poor prognosis in CCA patients. Functionally, NKILA facilitated CCA growth and metastasis in vitro and in vivo. The 5-methylcytosine (m⁵ C) methyltransferase NSUN2 interacts with NKILA, increasing its m⁵ C level and promoting its interaction with YBX1. Moreover, NKILA physically interacted with and suppressed miR-582-3p, which was regulated by METTL3-mediated N⁶ -methyladenosine (m⁶ A) modification. Finally, we showed that YAP1 was a target of NKILA via miR-582-3p and NKILA functioned partially via YAP1 in CCA. Taken together, our findings indicate a novel regulatory mechanism of NKILA for promoting CCA progression and that NKILA may be a promising target for CCA treatment.