Naturally occurring inorganic arsenic has been identified as a prominent causal agent in lung, bladder, liver, and prostate cancers. Although arsenic (As) has long been known to induce carcinogenicity via epigenetic mechanisms, alteration in histone gene expression has not been explored. The replication-dependent histone genes (also known as canonical histone genes) are the only genes found in multicellular organisms whose messenger RNA (mRNA) does not terminate with a poly(A) tail at the 3' end. Instead, they contain a conserved 26-nucleotide sequence that forms a stem-loop structure, and serves as the binding site for the Stem-loop binding protein (SLBP). SLBP is critical for canonical histone pre-mRNA processing and histone mRNA translation. Our previous studies demonstrated that arsenic exposure increases polyadenylation of histone H3.1 mRNA (a canonical histone H3) and its presence outside of S phase of the cell cycle due to the loss of SLBP protein and mRNA. Here we report that ectopic expression of polyadenylated H3.1 mRNA induces cell transformation and that the transformed cells are able to form tumors in athymic nude mice. These carcinogenic effects are dependent on the level of polyadenylation of canonical H3.1 mRNA. Notably, transfection of H3.1 cDNA with a stem-loop sequence in the front of the poly(A) signal generates less polyadenylated H3.1 mRNA and thereby attenuates cell transformation. Furthermore, the increase in polyadenylated H3.1 mRNA is able to antagonize histone H3.3 (a non-canonical variant of H3) in the promoter of active genes and perturb expression of cancer-related genes. In addition transfection of H3.1 with a poly(A) tail causes mitotic block in the cell cycle as well as chromosome instability. Furthermore, acute arsenic exposure by inhalation in mice results in the loss of SLBP and gain of polyadenylated H3.1 mRNA in lung tissues. These results suggest that the polyadenylation of canonical histone mRNAs induce by Arsenic is very disruptive to cellular genomic integrity and contributes to development of human cancers.

Citation Format: Qiao Yi Chen, Danqi Chen, Thomas Kluz, Feng Wu, Yusha Zhu, Thomas Des Marais, Jinquan Li, Xiaoru Zhang, Ashley Jordan, Hong Sun, Chunyuan Jin, Max Costa. Polyadenyaltion of canonical histone mRNA: A potential mechanism of arsenic-induced carcinogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 356.