Gadad, S.; Camacho, C. V.; Gong, X.; Thornton, M.; Malladi, V. S.; Nagari, A.; Sundaresan, A.; Nandu, T.; Koul, S.; Peng, Y.; Kraus, W. L.

Recent studies have demonstrated that a subset of long noncoding RNAs (lncRNAs) produce functional polypeptides and proteins. In this study, we discovered a 132 amino acid protein in human breast cancer cells named XCP (X-linked Cancer-associated Polypeptide), which is encoded by lncRNA1456 (a.k.a. RHOXF1P3), a transcript previously thought to be noncoding. lncRNA1456 is a pancreas- and testis-specific RNA whose gene is located on chromosome X. We found that the expression of lncRNA1456 and XCP are highly upregulated in the luminal A, luminal B, and HER2 molecular subtypes of breast cancer. XCP modulates both estrogen-dependent and estrogen-independent growth of breast cancer cells by regulating cancer pathways, as shown in cell and xenograft models. XCP shares some homology with homeodomain-containing proteins and interacts with the histone demethylase plant homeodomain finger protein 8 (PHF8), which is also encoded by an X-linked gene. Mechanistically, XCP stimulates the histone demethylase activity of PHF8 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.