SCIRT lncRNA Blocks the Shot of Breast Cancer Cells Self-Renewal Mechanism.

The study by Zagorac and colleagues represents an important step forward in the field of breast cancer, explaining a novel molecular mechanism of transition from slowly multiplying tumor-initiating cells (TIC) into their more differentiated version characterized by high proliferation. The mechanism involves the transcription factors SOX2 and EZH2, which directly repress transcription of cell-cycle genes and activate self-renewal genes in breast cancer cells. This mechanism is further controlled by a negative feedback loop mediated by a long noncoding RNA, SCIRT, not described previously, which is upregulated in tumorspheres and inhibits SOX2 and EZH2. SCIRT is an atypical tumor suppressor in breast cancer, being upregulated in cancer cells, but counteracting their aggressive phenotype. At the molecular level, by direct interaction with EZH2, SCIRT inhibits the transcriptional activity of EZH2 and "blocks the shot" of cancer cells' self-renewal. From a translational perspective, activating SCIRT or induction of SCIRT mimetics in breast cancer cells may lead to the dedifferentiation of TICs toward a less protumorigenic phenotype and a therapy-fragile state that could open new therapeutic avenues.See related article by Zagorac et al., p. 580. ©2021 American Association for Cancer Research.