Chondrosarcoma (CHS) is a rare and aggressive form of bone cancer characterized by its resistance to conventional therapies. The long non-coding RNA taurine up-regulated gene 1 (TUG1) has been reported to be implicated in various cancers; however, its role in CHS remains poorly understood.

This new research published in the Genes & Diseases journal by a team from Huazhong University of Science and Technology and Wuhan No.1 Hospital elucidates the mechanism by which TUG1 functions in CHS, revealing its role in the progression of CHS.

Using RT-qPCR analysis, the researchers discovered that TUG1 expression is significantly up-regulated in CHS cell lines. Subcellular fractionation and FISH assays further revealed that TUG1 is located in both the nucleus and cytoplasm. Knockdown studies demonstrated that silencing of TUG1 led to a notable decrease in CHS proliferation, migration, and invasion. The GEPIA database revealed a direct relationship between enhancer of zest homolog 2 (EZH2) and TUG1 expression. Subsequent RIP and RNA pull-down assays confirmed that TUG1 interacted with EZH2 to regulate its stability.

Further investigations by the research team revealed that DNA methyltransferase 3 beta (DNMT3B) is responsible for the m5C alteration of EZH2, while TUG1 enhances the stability of m5C-modified EZH2 RNA through the recruitment of ALYREF, a well-known RNA-binding protein. Additionally, this study suggests that TUG1 may suppress the expression of the tumor suppressor gene CPEB1 by promoting H3K27me3 enrichment at its promoter region through EZH2, likely leading to CHS progression.

Importantly, exosomal TUG1 enhanced the polarization of M2 tumor-associated macrophages, which increased the proliferation and metastasis of CHS. Furthermore, in vivo studies indicated that silencing lncRNA TUG1 inhibited M2 macrophage polarization and attenuated the tumorigenesis of CHS.

In conclusion, this study revealed the oncogenic role of TUG1 in CHS and its interactions with the downstream regulatory axis, offering novel insights into the tumorigenic mechanism of CHS.

Reference

Title of Original Paper: Long noncoding RNA TUG1 promotes chondrosarcoma progression and M2 polarization

Journal: Genes & Diseases

Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch.

DOI: https://doi.org/10.1016/j.gendis.2024.101474

Funding Information:

The National Natural Science Foundation of China (No. 82072978, 82274559, 82474545)
The Natural Science Foundation of Hubei Province, China (No. 2024AFB1011)
The China Postdoctoral Science Foundation (No. 2024T170247, 2024M750820)
The Natural Science Foundation of Wuhan, China (No. 2024040801020366)

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Genes & Diseases publishes rigorously peer-reviewed and high quality original articles and authoritative reviews that focus on the molecular bases of human diseases. Emphasis is placed on hypothesis-driven, mechanistic studies relevant to pathogenesis and/or experimental therapeutics of human diseases. The journal has worldwide authorship, and a broad scope in basic and translational biomedical research of molecular biology, molecular genetics, and cell biology, including but not limited to cell proliferation and apoptosis, signal transduction, stem cell biology, developmental biology, gene regulation and epigenetics, cancer biology, immunity and infection, neuroscience, disease-specific animal models, gene and cell-based therapies, and regenerative medicine.

Scopus CiteScore: 7.3 | Impact Factor: 6.9

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