Hexavalent chromium promotes malignant transformation via enhanced translation of SUV39H1.

Hexavalent chromium [Cr(VI)] is a widespread environmental carcinogen linked to lung cancer and other malignancies. Although genetic and epigenetic mechanisms of Cr(VI)-induced carcinogenesis have been extensively investigated, the role of translational control has remained largely unexplored. Here, we show that chronic low-dose Cr(VI) exposure in BEAS-2BR human bronchial epithelial cells activates eIF4E-driven cap-dependent translation through mTORC1-mediated phosphorylation and inactivation of the translational repressor 4E-BP1. Pharmacological inhibition of this pathway markedly suppresses Cr(VI)-induced cell transformation, cancer stem cell (CSC)-like properties, and DNA damage. Comparable inhibitory effects are observed following raptor knockdown, which disrupts mTORC1, or expression of a constitutively active non-phosphorylatable 4E-BP1 mutant. Notably, the histone methyltransferase SUV39H1 is selectively upregulated at the translational level and contributes to Cr(VI)-induced malignant phenotypes. Inhibition of the mTORC1/4E-BP1 signaling pathway, either pharmacologically or genetically, reduces SUV39H1 translation, whereas ectopic SUV39H1 expression restores CSC-like properties and DNA damage even in the presence of pathway inhibition. Together, these findings identify mTORC1/4E-BP1-mediated translational upregulation of SUV39H1 as an important mechanistic link in Cr(VI)-induced carcinogenesis, revealing a novel layer of regulation that integrates translational control with environmental carcinogen-induced epigenetic reprogramming.