m⁵C and m⁶A modification of long noncoding NKILA accelerates cholangiocarcinoma progression via the miR‐582‐3p‐YAP1 axis

Abstract

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 (m5C) methyltransferase NSUN2 interacts with NKILA, increasing its m5C 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 (m6A) 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.

Epitranscriptomic orchestrations: Unveiling the regulatory paradigm of m6A, A‐to‐I editing, and m5C in breast cancer via long noncoding RNAs and microRNAs

“…95 Previous studies have indicated the role of NSUN2 role in regulating lncRNA m5C methylation in esophageal squamous cell carcinoma, hepatocellular carcinoma (HCC), and cholangiocarcinoma. 45,94,96,97 However, the roles of NSUN2 methylated lncRNAs in BC are rarely clarified, which needs further investigation. Analysis of TCGA data, encompassing normal adjacent tissues and BRCA tumor tissues, revealed significant upregulation of NSUN2, NSUN5, DNMT1, DNMT3A, and DNMT3B, and downregulation of TRDMT1 and TET2 in BC, supported by protein-protein interaction networks and coexpression analysis, indicating internal correlations among m5C regulator genes.…”

“…As a crucial cytosine‐C(5)‐methyltransferase, NOP2/SUN RNA methyltransferase 2 (NSUN2) governs tumorigenesis and progression by influencing m5C modification in diverse RNAs, including mRNAs and lncRNAs 95 . Previous studies have indicated the role of NSUN2 role in regulating lncRNA m5C methylation in esophageal squamous cell carcinoma, hepatocellular carcinoma (HCC), and cholangiocarcinoma 45,94,96,97 . However, the roles of NSUN2 methylated lncRNAs in BC are rarely clarified, which needs further investigation.…”

Vital roles of m5C RNA modification in cancer and immune cell biology

“…YBX1 is another m 5 C reader that has multiple functions in cancer development and embryo development. Oncogenic effects of YBX1 are found in GC ( 51 ), bladder cancer ( 100 ), glioblastoma ( 101 ), CRC ( 76 , 102 ), cholangiocarcinoma ( 103 ), clear cell renal cell carcinoma (ccRCC) ( 104 ), prostate cancer ( 56 ), epithelial ovarian cancer ( 105 ) and cervical cancer ( 57 ), mainly owing to YBX1-RNA interactions that have stabilizing effects on target RNAs. For example, in GC patients, YBX1 binds with FOXC2 (Forkhead box protein C2) mRNA, which is m 5 C-modulated by NSUN2, to enhance its tumor-promoting ability ( 51 ).…”

“…The m 5 C levels of peripheral blood immune cells showed higher CRC diagnostic value than that of common blood tumor biomarkers ( 76 ), which is correlated with the discovery that m 5 C modification inhibits tumor infiltration of immune cells ( 133 ). In cholangiocarcinoma patients, the m 5 C-modified functional lncRNA NKILA (NF-kappa B interacting lncRNA), which is recognized and stabilized by YBX1, is associated with advanced TNM stage and poor prognosis ( 103 ). In glioma patients, m 5 C-associated genes, including NSUN1-5, NSUN7, DNMT1, DNMT3B and YBX-1, are upregulated, with the exception of NSUN6 ( 63 , 101 , 134 ).…”

Mitochondrial RNA modification: A novel therapeutic target to combat metastasis

“…It promotes hepatocellular carcinoma (HCC) cell migration, invasion, and angiogenesis by increasing the m 5 C modification of H19 long noncoding RNA (lncRNA) in the nucleolus, followed by promoting the binding of the m 5 C‐modified H19 long noncoding RNA (lncRNA) to the oncoprotein G3BP1 in the cytoplasm (Sun et al, 2020). NSUN2‐dependent m 5 C modification also participates in the metastasis of cholangiocarcinoma (CCA), another common primary liver cancer, by upregulating the level of m 5 C and promoting the interaction between m 5 C and YBX1 on NF‐kappa B interacting lncRNA (Zheng et al, 2022). Moreover, small ubiquitin‐like modifier‐2/3‐modified NSUN2 aggravates gastric cancer metastasis by regulating m 5 C modification on mRNA (Hu et al, 2021).…”