let-7 Modulates Chromatin Configuration and Target Gene Repression through Regulation of the ARID3B Complex

• let-7 regulates multiple steps in biogenesis of the ARID3B-ARID3A complex
• ARID3B complex recruits KDM4C for H3K9me3 demethylation at target genes
• ARID3B complex regulates the expression of stemness genes and let-7 target genes
• let-7-ARID3B axis is a prognostic indicator in human cancers

SummaryLet-7 is crucial for both stem cell differentiation and tumor suppression. Here, we demonstrate a chromatin-dependent mechanism of let-7 in regulating target gene expression in cancer cells. Let-7 directly represses the expression of AT-rich interacting domain 3B (ARID3B), ARID3A, and importin-9. In the absence of let-7, importin-9 facilitates the nuclear import of ARID3A, which then forms a complex with ARID3B. The nuclear ARID3B complex recruits histone demethylase 4C to reduce histone 3 lysine 9 trimethylation and promotes the transcription of stemness factors. Functionally, expression of ARID3B is critical for the tumor initiation in let-7-depleted cancer cells. An inverse association between let-7 and ARID3A/ARID3B and prognostic significance is demonstrated in head and neck cancer patients. These results highlight a chromatin-dependent mechanism where let-7 regulates cancer stemness through ARID3B.

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