Targeting Ribosome Biogenesis - FAM99B's Novel Role in Hepatocellular Carcinoma Treatment

Ribosome Biogenesis: A Cornerstone of Cancer Cell Proliferation

Hepatocellular carcinoma (HCC) ranks among the deadliest cancers globally, driven by unchecked cell proliferation and metastasis. At the heart of tumor growth lies ribosome biogenesis—a complex process responsible for producing ribosomes, the molecular machines essential for protein synthesis. Cancer cells hijack this process to fuel their rapid division and survival, creating a dependency that makes ribosome biogenesis a promising therapeutic target. However, traditional therapies often fail to address this vulnerability, leaving an urgent need for strategies that directly disrupt ribosome production in HCC.

Emerging research highlights long noncoding RNAs (lncRNAs) as master regulators of ribosome-related pathways. Among these, the liver-specific lncRNA FAM99B has emerged as a groundbreaking ribosome biogenesis inhibitor, offering a novel approach to starve HCC cells of their proliferative machinery.

FAM99B: A Key Regulator of Ribosome Function and HCC Suppression

The research underscores a notable downregulation of FAM99B expression in HCC tissues, correlating with poorer patient prognoses. This suggests a pivotal role for FAM99B in tumor suppression. Given FAM99B's primary localization within hepatocyte nuclei, its involvement in essential nuclear processes, including those related to ribosome function, is implicated. Functionally, FAM99B overexpression significantly inhibits HCC cell proliferation and metastasis, both in vitro and in vivo, highlighting its potential as a potent tumor suppressor.

Detailed experimental findings revealed that tumors derived from FAM99B-overexpressing cells exhibited significantly slower growth rates and reduced weights compared to control tumors. Additionally, Ki-67 staining indicated a markedly lower cell proliferation rate in FAM99B-overexpressing tumors. Furthermore, in an orthotopic xenograft mouse model, FAM99B overexpression dramatically suppressed HCC cell metastasis. These results collectively establish FAM99B as a bona fide tumor suppressor in HCC.

Fig 1 The liver-specific lncRNA FAM99B is downregulated in HCC and inhibits the proliferation and metastasis of HCC cells both and in vivo.¹

The FAM99B-DDX21 Interaction: A Novel Therapeutic Avenue Targeting Ribosomes

To elucidate the molecular mechanisms underlying FAM99B's tumor-suppressive effects, researchers identified its interaction with Dead-Box Helicase 21 (DDX21), a protein integral to ribosomal RNA processing and ribosome biogenesis. It was discovered that FAM99B binds to the C-terminal domain of DDX21. Overexpression of FAM99B led to a decrease in the protein level of DDX21, while knockdown of FAM99B resulted in an increase in DDX21 protein levels. This demonstrates FAM99B's capacity to downregulate DDX21 protein levels.

Further investigations revealed that FAM99B promotes the nuclear export of DDX21, facilitating its cleavage by caspase3/6 in the cytoplasm. This process effectively reduces DDX21 levels, subsequently inhibiting ribosome biogenesis and global protein synthesis. Given DDX21's reported role in promoting tumor progression in various cancers, its downregulation by FAM99B represents a critical mechanism in HCC suppression, with a direct consequence on the functionality of the ribosomes.

The study also explored the specific domains of FAM99B involved in this interaction. Through a series of truncation experiments, researchers identified the FAM99B^65-146 fragment as the critical region responsible for binding to DDX21. This fragment alone exhibited tumor-suppressive effects, mirroring the full-length FAM99B. This discovery opens new avenues for targeted therapeutic strategies, potentially utilizing this smaller, functional fragment to influence ribosome activity.

Targeting Ribosome Biogenesis: A Unique Therapeutic Strategy

Ribosome biogenesis, a fundamental process for protein synthesis, is frequently dysregulated in cancer. The study found that FAM99B, through its interaction with DDX21, significantly impacts this process. Overexpression of FAM99B led to the accumulation of pre-rRNAs and reductions in mature rRNAs, indicating a defect in rRNA processing. Additionally, FAM99B was found to regulate the expression of ribosomal proteins RPS29 and RPL38 at the transcriptional level.

Further experiments, including polysome profiling, demonstrated that FAM99B overexpression decreased the levels of 40S and 60S ribosomal subunits, indicating a direct impact on ribosome biogenesis. These findings suggest that FAM99B inhibits ribosome biogenesis by regulating rRNA processing and RPS29/RPL38 transcription via DDX21 in HCC cells.

Given the essential role of ribosomes in protein synthesis, disrupting ribosome biogenesis represents a compelling therapeutic strategy. By downregulating DDX21, FAM99B effectively suppresses global protein synthesis, thereby inhibiting HCC cell proliferation and metastasis. This mechanism underscores the potential of FAM99B as a novel therapeutic agent.

GalNAc-Conjugated FAM99B^65-146: A Promising Therapeutic Agent Targeting Ribosomes

The study further explored the therapeutic potential of the FAM99B^65-146 fragment by conjugating it with N-acetylgalactosamine (GalNAc). GalNAc enhances liver-specific delivery, making it an ideal carrier for therapeutic agents targeting HCC. The GalNAc-conjugated FAM99B^65-146 (GalNAc- FAM99B^65-146) demonstrated remarkable efficacy in inhibiting the growth and metastasis of orthotopic HCC xenografts.

This innovative approach represents a significant advancement in lncRNA-based gene therapy for HCC. By utilizing a truncated, functional fragment of FAM99B and enhancing its liver-specific delivery, researchers have developed a promising therapeutic agent that can modulate ribosome creation, and function.

Fig 2 Graphical illustration of the mechanism of FAM99B in HCC.¹

Conclusion: A New Frontier in HCC Treatment, Focusing on Ribosome Regulation

This study provides compelling evidence for the tumor-suppressive role of FAM99B in HCC. Through its interaction with DDX21, FAM99B effectively inhibits ribosome biogenesis and global protein synthesis, thereby suppressing HCC cell proliferation and metastasis. The identification of the FAM99B^65-146 fragment and its successful conjugation with GalNAc represent significant strides in developing novel therapeutic strategies for HCC, that focus on ribosome function.

This work not only advances the understanding of lncRNA biology but also opens new avenues for targeted therapies. The potential of FAM99B, and particularly the GalNAc- FAM99B^65-146 conjugate, as a therapeutic agent offers hope for improved treatment outcomes in HCC patients. Future research will undoubtedly build upon these findings, further exploring the clinical applications of FAM99B in combating this challenging disease, and the modulation of ribosomes.

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Reference

1. He, Yifei, et al. "The liver-specific long noncoding RNA FAM99B inhibits ribosome biogenesis and cancer progression through cleavage of dead-box Helicase 21." Cell Death & Disease 16.1 (2025): 97. https://doi.org/10.1038/s41419-025-07401-w. Distributed under the Open Access license CC BY 4.0, without modification.