# METTL3-mediated m6A methylation on lncRNA H19 inhibits intrahepatic cholangiocarcinoma progression through PPARγ downregulation

## TL;DR

This study shows that METTL3-mediated m6A methylation of the lncRNA H19 suppresses intrahepatic cholangiocarcinoma progression by downregulating PPARγ, suggesting a new treatment approach.

## Contribution

The novel finding is that METTL3 regulates H19 via m6A modification to inhibit ICCA through PPARγ suppression.

## Key findings

- METTL3 expression is reduced in ICCA and correlates with lower survival rates.
- METTL3 interacts with and methylates H19, inhibiting tumor cell proliferation and migration.
- An H19-armed oncolytic adenovirus combined with PPARγ inhibition shows strong antitumor effects.

## Abstract

Intrahepatic cholangiocarcinoma (ICCA), the second most prevalent primary liver malignancy, remains poorly understood at the molecular level. Research into the function of N6-methyladenosine (m6A) modification in the formation of ICCA and its potential as a therapeutic approach is being spurred by mounting evidence that it plays a crucial role in tumor biology. Immunohistochemical examination of patient samples in this investigation revealed a significant decrease in m6A methyltransferase METTL3 expression, accompanied by lower levels, which were associated with a lower overall survival rate. Functional assays demonstrated that the enforced expression of METTL3 inhibited ICCA cell proliferation and migration, while concurrently increasing the levels of the long non-coding RNA H19. Mechanistic experiments using RNA-binding protein immunoprecipitation and methylated RNA immunoprecipitation confirmed that METTL3 directly interacted with H19 and enhanced its m6A modification. Importantly, silencing of H19 reversed the growth- and migration-suppressive effects of METTL3, whereas H19 overexpression counteracted the phenotype induced by METTL3 downregulation. Further analysis revealed that the METTL3-H19 regulatory axis suppressed the expression of peroxisome proliferator-activated receptor gamma (PPARγ). Moreover, an oncolytic adenovirus engineered to overexpress H19, in combination with the PPARγ inhibitor BAY-4931, elicited potent antitumor effects both in vitro and in vivo. Collectively, these findings identify METTL3-mediated m6A modification of H19 as a critical suppressor of ICCA progression through modulation of PPARγ signaling. One interesting treatment option for ICCA may be the use of H19-armed oncolytic adenoviruses, especially when combined with PPARγ suppression.