# LL22NC03-N14H11.1 regulates the m6A modification of MYC and promotes glycolytic activity in hepatocellular carcinoma cells by inhibiting IGF2BP3 ubiquitination degradation

## TL;DR

This study shows how a specific long non-coding RNA promotes liver cancer by stabilizing a protein that boosts cancer cell growth and metabolism.

## Contribution

Identifies LL22NC03 as a novel regulator of HCC progression via the LL22NC03-IGF2BP3-MYC axis and m6A modification.

## Key findings

- LL22NC03 binds to and stabilizes IGF2BP3 by inhibiting its ubiquitination degradation.
- The LL22NC03-IGF2BP3 interaction promotes MYC transcription and glycolytic gene upregulation in HCC cells.
- This regulatory axis is critical for HCC proliferation, migration, and glycolytic activity.

## Abstract

Hepatocellular carcinoma (HCC) is the fifth leading cause of cancer-related mortality globally. Long non-coding RNAs (lncRNAs) are increasingly recognized for their pivotal roles in hepatocarcinogenesis. Specifically, the lncRNA LL22NC03-N14H11.1 (hereafter referred to as LL22NC03) has been characterized as a potent oncogenic factor in certain cancers. Therefore, our research aimed to investigate the involvement of LL22NC03 in HCC progression.

We analyzed the expression of IGF2BP3 in HCC specimens obtained from The Cancer Genome Atlas (TCGA) dataset. Further investigation via RNA pull-down and mass spectrometry analysis identified LL22NC03 as a binding partner of IGF2BP3, with LL22NC03 enhancing the stability of IGF2BP3 by inhibiting TRIM25-mediated ubiquitination. Subsequent in vitro and in vivo experiments were conducted to explore the modulation of LL22NC03 expression, in combination with manipulation of IGF2BP3 levels, which significantly impacted glycolysis, proliferation, migration, and invasiveness of HCC cells.

The study identified LL22NC03 as a promoter of HCC proliferation and migration of HCC cells. LL22NC03 was observed to bind to the ubiquitination site of IGF2BP3, thereby preventing its degradation and enhancing its stability. This interaction ultimately inhibited the degradation of IGF2BP3. Additionally, the interaction between LL22NC03 and IGF2BP3 facilitated the transcription of MYC, leading to the upregulation of glycolytic genes, including HK2, LDHA, GLUT1, PKM2, and PDK1. Finally, IGF2BP3 played a role in stabilizing MYC by recognizing N6-methyladenosine (m6A) modifications.

The LL22NC03-IGF2BP3-MYC regulatory axis is critically involved in the progression of HCC, suggesting its potential as a novel therapeutic target for this malignancy.

The online version contains supplementary material available at 10.1186/s13046-025-03606-1.