Epigenetic silencing of the tumor suppressor gene p15 by its antisense RNA is a key mechanism in cancer development. The study shows that antisense RNA, specifically p15 antisense (p15AS), can induce gene silencing through heterochromatin formation and DNA methylation. This process occurs both in cis and trans, and is independent of Dicer. The p15AS RNA was found to be naturally expressed in leukemia cells, and its expression correlates with reduced p15 expression. The antisense RNA induces silencing of the p15 gene, leading to increased cell growth in mouse embryonic stem cells. The study also demonstrates that p15AS-induced silencing is stable and can persist even after the antisense RNA is turned off. The mechanism involves changes in histone modifications, specifically increased H3K9 dimethylation and decreased H3K4 dimethylation, which are associated with heterochromatin formation. These findings suggest that antisense RNA may play a role in epigenetic silencing of tumor suppressor genes in cancer. The study also highlights the potential of antisense RNA as a molecular marker for cancer risk assessment and as a therapeutic target. The results provide evidence for the role of antisense RNA in gene silencing through heterochromatin formation and DNA methylation, and suggest that this process may be a key factor in tumorigenesis. The study also shows that the effects of antisense RNA on gene expression are stable and can persist even after the antisense RNA is no longer expressed. The findings have important implications for understanding the epigenetic mechanisms underlying cancer development and for developing new therapeutic strategies.Epigenetic silencing of the tumor suppressor gene p15 by its antisense RNA is a key mechanism in cancer development. The study shows that antisense RNA, specifically p15 antisense (p15AS), can induce gene silencing through heterochromatin formation and DNA methylation. This process occurs both in cis and trans, and is independent of Dicer. The p15AS RNA was found to be naturally expressed in leukemia cells, and its expression correlates with reduced p15 expression. The antisense RNA induces silencing of the p15 gene, leading to increased cell growth in mouse embryonic stem cells. The study also demonstrates that p15AS-induced silencing is stable and can persist even after the antisense RNA is turned off. The mechanism involves changes in histone modifications, specifically increased H3K9 dimethylation and decreased H3K4 dimethylation, which are associated with heterochromatin formation. These findings suggest that antisense RNA may play a role in epigenetic silencing of tumor suppressor genes in cancer. The study also highlights the potential of antisense RNA as a molecular marker for cancer risk assessment and as a therapeutic target. The results provide evidence for the role of antisense RNA in gene silencing through heterochromatin formation and DNA methylation, and suggest that this process may be a key factor in tumorigenesis. The study also shows that the effects of antisense RNA on gene expression are stable and can persist even after the antisense RNA is no longer expressed. The findings have important implications for understanding the epigenetic mechanisms underlying cancer development and for developing new therapeutic strategies.