PRMT1-mediated methylation of ME2 promotes hepatocellular carcinoma growth by inhibiting ubiquitination

Sep 21, 2026

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Primary liver cancer remains highly lethal, with hepatocellular carcinoma (HCC) showing low 5-year survival despite multiple therapies because the disease advances rapidly and develops drug resistance. This study investigates how PRMT1-driven methylation regulates HCC progression, focusing on the mitochondrial NADP+-dependent malic enzyme ME2. ME2 is activated by PRMT1-mediated methylation at R67, strengthening redox homeostasis and supporting tumor growth while suppressing ubiquitination-related control of ME2 function.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages16

Reading Time40 min

AccessFree to download

Introduction

Epigenetic regulation and PRMT1

Metabolic reprogramming in HCC and ME2

Study focus

[www.nature.com/cddis](www.nature.com/cddis) ARTICLE OPEN PRMT1-mediated methylation of ME2 promotes hepatocellular carcinoma growth by inhibiting ubiquitination Shuai Zhang 1,2,6, Shuling Zhang 1,6, Baijuan Xia3,6, Xueying Li4, Hongyu Jiang5, Su Feng5, Yang Xiang3, Ya Qiu 1, Shi Zhou 2 ✉ and Peng Luo 1 ✉ © The Author(s) 2024 INTRODUCTION Primary liver cancer ranks second internationally in terms of cancer-related mortality and is the seventh most prevalent tumor. Its incidence is increasing annually [1] . Globally, more than 906,000 people received a liver cancer diagnosis in 2020 . Hepatocellular carcinoma (HCC), which affects approximately 75% of liver cancer patients, is the most common type of liver cancer [2]. The 5-year survival rate for patients with hepatocellular carcinoma remains low despite the availability of a variety of treatment options, such as targeted therapy, radiotherapy, immunotherapy, and surgical resection. This is because HCC progresses quickly and is prone to drug resistance [3] . To improve the clinical prognosis of HCC patients, it is crucial to decipher how key clinical and molecular features inﬂuence the patient’s disease course and response to treatment. Hepatocellular carcinoma is associated with issues related to liver metabolism, as the liver is an organ engaged in metabolism [4] . Cellular metabolic reprogramming has been identiﬁed as oneof the hallmarks of cancer [5] . As a tumor progresses, tumor metabolism may have an impact on the phenotype of cancer cells and promote their aggressiveness [6] . An increasing body of research indicates that abnormal expression of metabolic enzymes plays a major role in the growth of tumor cells [7, 8] . According to previous studies, excessive hyperglycemia promotes HCC spread through the nuclear translocation of the metabolic enzyme PKM2, which strengthens the immunosuppressive environment [9] . In addition, tumor development is inhibited by TERT dephosphorylation and inhibited by fructose 1,6-bisphosphatase 1 [10] . A class of oxidative decarboxylases known as malic enzymes catalyzes the breakdown of malate into CO2 and pyruvate as well as the generation of the dinucleotide cofactors NAD+ and NADP+, which are necessary for glycolysis, gluconeogenesis, and fatty acid synthesis [11]. The tetrameric protein known as malic enzyme (ME) has a highly conserved amino acid sequence and structure [12] . In mammalian cells, three isoforms of ME have been identiﬁed: mitochondrial NADP+-dependent isozyme (ME2), cytoplasmic NADP+-dependent isozyme (ME1), and mitochondrial NADP + -dependent isozyme (ME3) . The two primary isoforms of ME are ME1 and ME2 [13] . Among these, ME2 is more prevalent in cells and regulates cellular metabolism more than ME1 or ME3. The carbon skeleton, cellular energy requirements, and reducing equivalents are all factors that ME2 regulates TCA ﬂux for [13, 14] . Furthermore, ME2 markedly improves lipid and glutamine metabolism in cancer cells, satisfying the high metabolic requirements of cancer cells [13] . ME2 is associated with the development of malignancies and is variably expressed in a number of cancers [15–20] . The generation of NADPH and its redox-control ability endow ME2 with powerful oncogenic functions. However, the mechanism of action of ME2 in HCC has rarely been reported. Histone modiﬁcations, noncoding RNA regulation, and DNA methylation make up the majority of epigenetic control. With the rapid development of the ﬁeld of epigenetics, the functions and 1Department of Nutrition and Food Hygiene, School of Public Health, Guizhou Medical University, 561113 Guiyang, Guizhou, P. R. China. 2Department of Interventional Radiology, the Afﬁliated Hospital of Guizhou Medical University, 550004 Guiyang, Guizhou, P. R. China. 3School of Basic Medical Sciences, Guizhou Medical University, 561113 Guiyang, Guizhou, P. R. China. 4Department of Radiology, Guiyang Public Health Clinical Center, No.6 Daying Road, Yunyan

FAQs

Why is hepatocellular carcinoma difficult to treat effectively?

HCC progresses quickly and is prone to drug resistance, which limits the long-term effectiveness of targeted therapy, radiotherapy, immunotherapy, and surgical resection.

What role does ME2 play in cancer metabolism?

ME2 regulates TCA flux and supports high metabolic demands in cancer cells by improving lipid and glutamine metabolism and producing NADPH, contributing to oncogenic functions.

How does PRMT1-mediated methylation affect ME2 in HCC?

PRMT1 methylates ME2 at the R67 position, activating ME2 to enhance redox homeostasis and promote HCC growth by inhibiting ubiquitination-related regulation.

Sep 21, 2026

Uploaded by Eden