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

Tsai-Tsen Liao; Wen-Hao Hsu; Chien-Hsin Ho; Wei-Lun Hwang; Hsin-Yi Lan; Ting Lo; Cheng-Chi Chang; Shyh-Kuan Tai; Muh-Hwa Yang

doi:10.1016/j.celrep.2015.12.064

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

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

Authors

Tsai-Tsen Liao¹, Wen-Hao Hsu¹, Chien-Hsin Ho¹, Wei-Lun Hwang², Hsin-Yi Lan¹, Ting Lo¹, Cheng-Chi Chang³, Shyh-Kuan Tai⁴, Muh-Hwa Yang⁵

Affiliations

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.

PMID: 26776511
DOI: 10.1016/j.celrep.2015.12.064

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Base Sequence
Cell Line
Chromatin / metabolism
DNA-Binding Proteins / antagonists & inhibitors
DNA-Binding Proteins / genetics
DNA-Binding Proteins / metabolism*
Female
Histones / metabolism
Humans
Karyopherins / chemistry
Karyopherins / genetics
Karyopherins / metabolism
Mice
Mice, Inbred BALB C
Mice, Nude
MicroRNAs / antagonists & inhibitors
MicroRNAs / genetics
MicroRNAs / metabolism*
Neoplasms / metabolism
Neoplasms / mortality
Neoplasms / pathology
Octamer Transcription Factor-3 / genetics
Oligonucleotides, Antisense / metabolism
RNA Interference
Sequence Alignment
Transcription Factors / genetics
Transcription Factors / metabolism
Transcriptome
Transplantation, Heterologous

Substances

ARID3A protein, human
ARID3B protein, human
Chromatin
DNA-Binding Proteins
Histones
IPO9 protein, human
Karyopherins
MicroRNAs
Octamer Transcription Factor-3
Oligonucleotides, Antisense
POU5F1 protein, human
Transcription Factors
mirnlet7 microRNA, human