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Cell Rep. 2016 Jan 26;14(3):520-533. doi: 10.1016/j.celrep.2015.12.064. Epub 2016 Jan 14.

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

Author information

1
Institute of Clinical Medicine, National Yang-Ming University, No. 155, Section 2, Li-Nong Street, Taipei 11221, Taiwan.
2
The Ph.D. Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, No. 250, Wuxing Street, Taipei 11031, Taiwan.
3
Graduate Institute of Oral Biology, School of Dentistry, National Taiwan University, No. 1, Changde Street, Taipei 10048, Taiwan.
4
Department of Otolaryngology, Taipei Veterans General Hospital, No. 201, Section 2, Shih-Pai Road, Taipei 11217, Taiwan.
5
Institute of Clinical Medicine, National Yang-Ming University, No. 155, Section 2, Li-Nong Street, Taipei 11221, Taiwan; Institute of Biotechnology in Medicine, National Yang-Ming University, No. 155, Section 2, Li-Nong Street, Taipei 11221, Taiwan; Genomic Research Center, National Yang-Ming University, No. 155, Section 2, Li-Nong Street, Taipei 11221, Taiwan; Division of Medical Oncology, Department of Oncology, Taipei Veterans General Hospital, No. 201, Section 2, Shih-Pai Road, Taipei 11217, Taiwan; Genomic Research Center, Academia Sinica, No. 128, Section 2, Academia Road, Taipei 11529, Taiwan. Electronic address: mhyang2@vghtpe.gov.tw.

Abstract

Let-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.

PMID:
26776511
DOI:
10.1016/j.celrep.2015.12.064
[Indexed for MEDLINE]
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