Recently, Guangyong Ma's group in the National Key Laboratory of Multi-target Natural Medicines of the University of China, in collaboration with Prof. Masao Matsuoka of Kumamoto University, Japan, published a research paper entitled ‘Identification of AK4 and RHOC as potential oncogenes addicted by adult T cell leukemia’. Benquan Liu, a PhD student in our university's class of 2020, is the paper's first author, and China Pharmaceutical University is the first corresponding institution.
Human T-cell leukemia type 1 (HTLV-1), the first human oncogenic retrovirus discovered worldwide, can cause adult T-cell leukemia (ATL) by infection. The disease is characterised by malignant T-cell proliferation, immune system collapse and high lethality. HTLV-1 achieves long-term latency by integrating the viral genome into the host CD4+ T-cell DNA, and its antisense strand encoding the HBZ protein is considered to be a central driver of disease progression. HBZ has become a focus of research in recent years by affecting the functions of host transcription factors, interfering with the regulation of the cell cycle, and facilitating the viral latency. HBZ has become a focus of research in recent years. In the field of gene regulation, microRNAs (miRNAs), a class of non-coding RNAs about 22 nucleotides in length, play a key role in metabolic reprogramming of cancer by regulating gene expression through targeted binding of mRNAs.
The team found that HBZ was able to significantly inhibit the expression of host miR-455 in HBZ stably transduced cells, a phenomenon that is highly conserved in ATL patients. The research team further combined RNA-seq and miRNA target prediction techniques to target adenylate kinase 4 (AK4) and RhoC GTPase (RHOC) as direct target genes of miR-455, revealing the molecular pathway of HBZ remodelling the host gene network through miRNA. Based on joint multi-omics analysis, the aberrant expression of AK4 and RHOC was found to affect multiple pathways such as MYC, oxidative phosphorylation, and mTORC1 fatty acid metabolism, which may contribute to the malignant phenotype of ATL cells.
Notably, the research team detected abnormally elevated sphingomyelin content in ATL cells, and inhibitors of sphingomyelin synthesis significantly inhibited the proliferation of cancer cells, a finding that provides a novel perspective for the treatment of ATL. The results not only elucidated the molecular mechanism of HBZ regulating metabolism and signalling pathways through miR-455-AK4/RHOC axis, but also directly linked sphingolipid metabolism with ATL progression for the first time, suggesting that targeting sphingolipid synthesis pathway may become a key strategy to break through the existing therapeutic dilemmas, and laying a theoretical foundation for the development of precision therapies.
This research work was supported by the National Natural Science Foundation of China under the grant of top-level project and the research project of high-level introduced talents of China Pharmaceutical University.
Link to the paper: www.pnas.org/doi/10.1073/pnas.2416412122.
