X-Linked Cancer-Associated Polypeptide, Encoded by a Putative Noncoding RNA, Regulates Gene Expression and Cellular Pathways in Breast Cancer [RNA-seq]

Long noncoding RNAs (lncRNAs) have been found to play a critical role in cancer biology and other prevalent diseases. While most lncRNAs are poorly conserved and not evolutionarily neutral, they regulate biological processes at the RNA level. Recent studies have suggested that a subset of lncRNAs produce functional proteins, and in this study, we have discovered a protein named XCP ((X-linked Cancer-associated Polypeptide). XCP is encoded by a pancreas- and testis-specific RNA annotated as a putative long noncoding RNA by Sun and Gadad et al. (lncRNA1456, aka RHOXF1P3), located on chromosome X. We found that lncRNA1456 and XCP are upregulated in luminal A, luminal B, and HER2 molecular subtypes of breast cancer, and XCP modulates estrogen-dependent as well as estrogen-independent growth of MCF-7 cells by regulating cancer pathways in xenograft models. We find that XCP shares homology with homeodomain-containing proteins and interacts with PHF8, which is also an X-linked gene, and demethylates H3K9me2 to activate transcription. Mechanistically, XCP positively regulates histone demethylase activity of PHF8 in vitro to regulate gene expression in breast cancer cells. These findings identify XCP as a coregulator of transcription and emphasize the need to interrogate the potential functional roles of open reading frames originating from noncoding RNAs.