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The Liver-Enriched Long Non-Coding RNA FAM99A Suppresses Tumorigenesis through Negative Regulation of Protein Synthesis
Journal article   Open access   Peer reviewed

The Liver-Enriched Long Non-Coding RNA FAM99A Suppresses Tumorigenesis through Negative Regulation of Protein Synthesis

Nima Sarfaraz, Ranjit Kaur, Sky Harper, Lilly Oni, Srinivas Somarowthu and Michael J. Bouchard
Journal of molecular biology, v 438(6), 169653
23 Jan 2026
DOI: https://doi.org/10.1016/j.jmb.2026.169653
PMID: 41581654
url
https://doi.org/10.1016/j.jmb.2026.169653View
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Abstract

FAM99A Hepatocellular Carcinoma LncRNA Ribosome Tumor Suppressor Liver Cancer Translation
[Display omitted] •FAM99A is a liver-enriched lncRNA downregulated across liver cancer subtypes.•FAM99A expression declines during primary hepatocyte dedifferentiation and HBV infection.•FAM99A-203 is the predominant isoform with altered splicing patterns in tumors.•FAM99A suppresses cellular protein synthesis rates and anchorage-independent growth.•FAM99A interacts with translation initiation factors and RNA helicases. Primary liver cancer represents a significant global health burden, with limited therapeutic options for advanced disease. Long non-coding RNAs (lncRNAs) are increasingly found to play crucial roles in hepatic biology and disease progression. Here, we identify FAM99A as a highly liver-enriched lncRNA that is systematically downregulated across liver malignancies, with reduced expression correlating with poor clinical outcomes. FAM99A exhibits remarkable tissue specificity with minimal expression outside the liver, and its levels rapidly decline during primary hepatocyte dedifferentiation in culture. Through isoform analysis, we establish FAM99A-203 as the predominant transcript in normal liver tissue and observe altered isoform distribution in liver cancers. Functionally, FAM99A overexpression inhibits anchorage-independent growth in liver cancer cell lines. Transcriptomic analysis reveals that FAM99A negatively regulates translation-related pathways in both liver cancer cells and primary hepatocytes. This is corroborated by protein synthesis assays showing that FAM99A overexpression substantially reduces global translation rates. Targeted RNase H-mediated extraction coupled with mass spectrometry identifies multiple components of the translation machinery as direct FAM99A binding partners, including eukaryotic translation initiation factors and RNA helicases involved in ribosome biogenesis. Clinical data analysis demonstrates significant inverse correlations between FAM99A expression and ribosomal protein genes in liver cancer patients. Additionally, hepatitis B virus appears to downregulate FAM99A expression, potentially contributing to its oncogenic properties. Our findings establish FAM99A as a liver-enriched translational regulator that exerts tumor-suppressive effects by restraining protein synthesis rates, offering insights into hepatocarcinogenesis and the potential of FAM99A as both a biomarker and agent in new therapeutic avenues.

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