Kannanganattu V. Prasanth, professor of cell and developmental biology, and members of his lab investigate the regulation of gene expression and RNA biology with a focus on cancer. In a new article published in eLife, “The S-phase-induced lncRNA SUNO1 promotes cell proliferation by controlling YAP1/Hippo signaling pathway,” Prasanth and fellow researchers detail the role of long noncoding RNAs in cell cycle progression.
The cell cycle is a tightly regulated process. Deviations from the cycle lead to aberrant cell growth, which is linked to cancer. Because, mutations in the cell cycle have such harmful effects, proteins responsible for cell cycle regulation are heavily researched. However, the role of long noncoding RNAs (lncRNAs) in cell cycle progression has not been studied as thoroughly.
While the human genome encodes lncRNA genes, not much is known about their functions. In a collaborative effort, the researchers identified lncRNAs that exhibited differential expression, similar to protein-coding genes, during cell cycle. The lab isolated cells at different stages of the cell cycle and performed RNA sequencing analyses to identify lncRNAs that were differentially expressed during specific cell cycle stages. They identified nearly 2,000 lncRNA genes that showed differential expression at various stages of the cell cycle; they focused on characterizing the role of one of the S-phase up-regulated lncRNA, which is linked with cell growth and when deregulated, associated with cancer. This particular study is a steppingstone for the characterization of cell-cycle regulated lncRNAs and will be critical for understanding signaling steps in cancer progression as well as normal cellular development, according to Prasanth.
By modulating the expression of genes that control cell proliferation through gene knockdown experiments, investigators searched for genes that played a role in cell cycle progression. After performing phenotypic screen upon knock down of several cell cycle-regulated lncRNAs, they identified SUNO1, a low copy lncRNA that only produces 5-10 transcripts per cell, to be upregulated in S-phase. The gene plays a critical role in facilitating cell cycle progression. Given its low copy number, this was quite surprising for the research group. Their studies revealed that SUNO1 facilitates cell proliferation by promoting the oncogenic YAP1 (Yes-Associated protein 1) transcription co-activator-mediated gene expression.
In addition to S-phase, SUNO1 was also upregulated during DNA damage. Aberrant DNA damage, as well as uncontrolled growth during S-phase, may cause cancer. The research group found that elevated levels of SUNO1 are associated with poor cancer prognosis and tumorigenesis, making it a potential marker for diagnosis. Looking beyond SUNO1, Prof. Prasanth said the major focus of his lab is to investigate the roles of novel lncRNAs in the cell cycle and cancer progression.
