The m(7)G Reader NCBP2 Promotes Pancreatic Cancer Progression by Upregulating MAPK/ERK Signaling

SIMPLE SUMMARY: N7-methylguanosine (m(7)G) methylation plays an important role in the development of pancreatic adenocarcinoma (PDAC). Among the 29 regulatory genes of m(7)G methylation, they can be roughly divided into three categories: methyltransferase (writer), demethylase (eraser), and binding protein (reader) according to their functions. In this study, we explore the role of m(7)G reader NCBP2 in PDAC progression: NCBP2 activates MEK/ERK signaling by upregulating c-JUN, thereby promoting PDAC cell proliferation. In summary, we identify a novel potential therapeutic target for PDAC, which sheds new light on the treatment of PDAC patients. ABSTRACT: PDAC is one of the most common malignant tumors worldwide. The difficulty of early diagnosis and lack of effective treatment are the main reasons for its poor prognosis. Therefore, it is urgent to identify novel diagnostic and therapeutic targets for PDAC patients. The m(7)G methylation is a common type of RNA modification that plays a pivotal role in regulating tumor development. However, the correlation between m(7)G regulatory genes and PDAC progression remains unclear. By integrating gene expression and related clinical information of PDAC patients from TCGA and GEO cohorts, m(7)G binding protein NCBP2 was found to be highly expressed in PDAC patients. More importantly, PDAC patients with high NCBP2 expression had a worse prognosis. Stable NCBP2-knockdown and overexpression PDAC cell lines were constructed to further perform in-vitro and in-vivo experiments. NCBP2-knockdown significantly inhibited PDAC cell proliferation, while overexpression of NCBP2 dramatically promoted PDAC cell growth. Mechanistically, NCBP2 enhanced the translation of c-JUN, which in turn activated MEK/ERK signaling to promote PDAC progression. In conclusion, our study reveals that m(7)G reader NCBP2 promotes PDAC progression by activating MEK/ERK pathway, which could serve as a novel therapeutic target for PDAC patients.