iNature
Intrahepatic cholangiocarcinoma (iCCA) is a fatal malignancy of the biliary system. Lack of detailed understanding of oncogenic signaling or global gene expression alterations hinders the diagnosis and treatment of clinical iCCA. Protein lactation is a newly discovered post-translational modification that coordinates gene expression and remains elusive in the pathogenesis of iCCA.
2024年4月26日，空军军医大学陶开山及贾林涛共同通讯在Journal of Hepatology（IF=26）在线发表题为“Nucleolin lactylation contributes to intrahepatic cholangiocarcinoma pathogenesis via RNA splicing regulation of MADD ”的研究论文，该研究表明核蛋白乳酸化通过RNA剪接调控MADD参与肝内胆管癌的发病。 核蛋白(Nucleolin, NCL)是核核中最丰富的RNA结合蛋白，被认为是与iCCA发生和发展相关的功能性乳酸化靶点。 在糖酵解过度活跃的情况下，NCL主要在赖氨酸477位点被酰基转移酶P300乳酸化，并促进iCCA细胞的增殖和侵袭。
Mechanistically, lactated NCLs bind to the primary transcript of the MAP kinase-activated death domain protein (MADD) and guarantee efficient translation of MADD by avoiding the generation of premature stop codons. NCL lactation, MADD, and subsequent ERK activation promote xenograft tumor growth and have been found to correlate with overall survival in patients with iCCA. In conclusion, NCL upregulates MADD through the RNA splicing-dependent mechanism lactation, thereby enhancing the pathogenesis of iCCA through the MAPK pathway.
Intrahepatic cholangiocarcinoma (iCCA) is a rare, primary, highly aggressive liver malignancy that arises from intrahepatic and extrahepatic bile duct epithelial cells. Despite the increasing incidence worldwide, optimal diagnosis and management of iCCA remains a daunting challenge to date due to the lack of potential treatment options.
While the majority of iCCAs are de onset and have no identifiable risk factors, chromosomal mutations have been mapped to typical cancer-associated loci, including KRAS, TP53, IDH1/2, BAP1, MDM2, and FGFR2, which lead to overactivity of oncogenic signals, such as MAPK and PI3K/AKT pathways. These genetic alterations eventually lead to widespread dysregulation of genes through aberrant activation of transcription factors such as CDX2, TTF1, GATA3, and PAX8. However, a growing body of research has shown that other mechanisms play an integral role in the development of iCCA, in addition to gene transcriptional regulation.
In particular, alternative splicing (AS) during pre-mRNA maturation, which is due to mutations that produce or disrupt splice sites, aberrant expression of splice factors, and impaired signaling pathways that affect the activity of splice events, has been shown to fine-tune the gene expression profile of iCCA. In addition, post-translational modifications, such as glycosylation of FGFRs or hnRNP-K and ubiquitination/deubiquitination of key regulators such as BAP1, have also been shown to underlie the pathogenesis of iCCA, increasing the complexity of stratification and multi-level regulation of aberrant gene expression.
In the past 3 years, a novel post-translational modification, protein lactation, has been discovered, which is involved in various physiological and pathological processes. On histones, the addition of lactate groups to lysine residues was first reported, representing a novel epigenetic pattern that drives gene transcription. However, it was later discovered that so-called lactation of lysine was prevalent in non-histone proteins. The most common donor for lactation is lactate, the end product of glycolysis, thus redefining it from a metabolic waste or energy source as a key regulator of gene expression and protein function.
Lactated proteins are distributed in multiple subcellular compartments and are closely related to a variety of biological processes, including mRNA splicing, glycolysis, aminoacyl-tRNAs biosynthesis, RNA transport, and many signaling pathways. Thus, protein lactation has been identified to play an important role in inflammation, neurodevelopment, and tumor development. In the case of tumorigenesis, lactation may also provide a direct link between metabolic reprogramming and complex signaling networks that underlie gene deregulation and cancer characterization. However, lactase in most malignancies remains to be studied, and the role of protein lactation in cancer initiation and progression remains largely elusive.
机理模式图（图源自Journal of Hepatology ）
The study used mass spectrometry to screen for differential lactated proteins between clinical iCCA and adjacent tissues and identified nucleoprotein (NCL) as a novel lactated substrate that promotes cholangiocarcinoma. Mechanistically, lactation of NCL on lysine 477 is required to inhibit the activity of MAP kinase-activated 5' splicing of death domain protein (MADD) transcripts, which results in undesired termination of protein synthesis. Thus, lactated NCLs upregulate MADD, and MADD, as a receptor protein, subsequently transmits signals from transmembrane receptors to mitogen-activated protein kinases (MARKs) and promotes the development of iCCAs. The results of this study reveal a novel link between metabolic reprogramming and typical tumor initiation events, and provide biomarkers that may be used for prognostic assessment or targeted therapy of iCCA.
Original link:
https://doi.org/10.1016/j.jhep.2024.04.010
来源:iNature