RARβ acts as both an upstream regulator and downstream effector of miR-22, which epigenetically regulates NUR77 to induce apoptosis of colon cancer cells

Ying Hu, Samuel W. French, Thinh Chau, Hui Xin Liu, Lili Sheng, Fang Wei, Jesse L Stondell, Juan Carlos Garcia, Yanlei Du, Christopher Bowlus, Yu-Jui Yvonne Wan

Research output: Contribution to journalArticle

Abstract

This study investigates the mechanism and consequences of microRNA-22 ( miR-22) induction. Our data revealed for the first time that retinoic acid (RA) and histone deacetylase (HDAC) inhibitors, including short-chain fatty acids and suberanilohydroxamic acid (SAHA), could individually or in combination induce miR-22. This induction was mediated via RA receptor β (RARβ) binding to a direct repeat 5 (DR5) motif. In addition, we uncovered HDAC1 as a novel miR-22 target. In an miR-22-dependent manner, HDAC inhibitors and RA reduced HDAC1, HDAC4, and sirtuin 1 (SIRT1), which were involved in chromatin remodeling of the RARβ and nerve growth factor IB ( NUR77). Thus, HDAC inhibitors and RA-induced miR-22 resulted in simultaneous induction of cytoplasmic RARβ and NUR77, leading to apoptosis of colon cancer cells. In mice, miR-22 and its inducers inhibited the growth of xenograft colon cancer. Moreover, tumor size reduction was accompanied by elevated miR-22, NUR77, and RARβ and by reduced HDACs. In human colon polyps and adenocarcinomas, miR-22 and RARβ were consistently reduced, which was associated with elevated HDAC1, HDAC4, and SIRT1 in colon adenocarcinomas. Results from this study revealed a novel anticancer mechanism of RARβ via miR-22 induction to epigenetically regulate itself and NUR77, providing a promising cancer treatment modality using miR-22 and its inducers.-Hu, Y., French, S. W., Chau, T., Liu, H.-X., Sheng, L., Wei, F., Stondell, J., Garcia, J. C., Du, Y., Bowlus, C. L., Wan, Y.-J. Y. RARβ acts as both an upstream regulator and downstream effector of miR-22, which epigenetically regulates NUR77 to induce apoptosis of colon cancer cells.

Original languageEnglish (US)
Pages (from-to)2314-2326
Number of pages13
JournalFASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume33
Issue number2
DOIs
StatePublished - Feb 1 2019

Fingerprint

MicroRNAs
Colonic Neoplasms
Cells
Apoptosis
Histone Deacetylase Inhibitors
Sirtuin 1
Tretinoin
Colon
Adenocarcinoma
Nerve Growth Factor Receptor
Retinoic Acid Receptors
Chromatin Assembly and Disassembly
Oncology
Volatile Fatty Acids
Nucleic Acid Repetitive Sequences
Cytoplasmic and Nuclear Receptors
Polyps
Heterografts
Chromatin
Tumors

Keywords

  • butyrate
  • nuclear receptor
  • propionate
  • protein deacetylase
  • short-chain fatty acid

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

Cite this

@article{232abe576a4b44f6a513a1d0c6e67365,
title = "RARβ acts as both an upstream regulator and downstream effector of miR-22, which epigenetically regulates NUR77 to induce apoptosis of colon cancer cells",
abstract = "This study investigates the mechanism and consequences of microRNA-22 ( miR-22) induction. Our data revealed for the first time that retinoic acid (RA) and histone deacetylase (HDAC) inhibitors, including short-chain fatty acids and suberanilohydroxamic acid (SAHA), could individually or in combination induce miR-22. This induction was mediated via RA receptor β (RARβ) binding to a direct repeat 5 (DR5) motif. In addition, we uncovered HDAC1 as a novel miR-22 target. In an miR-22-dependent manner, HDAC inhibitors and RA reduced HDAC1, HDAC4, and sirtuin 1 (SIRT1), which were involved in chromatin remodeling of the RARβ and nerve growth factor IB ( NUR77). Thus, HDAC inhibitors and RA-induced miR-22 resulted in simultaneous induction of cytoplasmic RARβ and NUR77, leading to apoptosis of colon cancer cells. In mice, miR-22 and its inducers inhibited the growth of xenograft colon cancer. Moreover, tumor size reduction was accompanied by elevated miR-22, NUR77, and RARβ and by reduced HDACs. In human colon polyps and adenocarcinomas, miR-22 and RARβ were consistently reduced, which was associated with elevated HDAC1, HDAC4, and SIRT1 in colon adenocarcinomas. Results from this study revealed a novel anticancer mechanism of RARβ via miR-22 induction to epigenetically regulate itself and NUR77, providing a promising cancer treatment modality using miR-22 and its inducers.-Hu, Y., French, S. W., Chau, T., Liu, H.-X., Sheng, L., Wei, F., Stondell, J., Garcia, J. C., Du, Y., Bowlus, C. L., Wan, Y.-J. Y. RARβ acts as both an upstream regulator and downstream effector of miR-22, which epigenetically regulates NUR77 to induce apoptosis of colon cancer cells.",
keywords = "butyrate, nuclear receptor, propionate, protein deacetylase, short-chain fatty acid",
author = "Ying Hu and French, {Samuel W.} and Thinh Chau and Liu, {Hui Xin} and Lili Sheng and Fang Wei and Stondell, {Jesse L} and Garcia, {Juan Carlos} and Yanlei Du and Christopher Bowlus and Wan, {Yu-Jui Yvonne}",
year = "2019",
month = "2",
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doi = "10.1096/fj.201801390R",
language = "English (US)",
volume = "33",
pages = "2314--2326",
journal = "FASEB Journal",
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publisher = "FASEB",
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TY - JOUR

T1 - RARβ acts as both an upstream regulator and downstream effector of miR-22, which epigenetically regulates NUR77 to induce apoptosis of colon cancer cells

AU - Hu, Ying

AU - French, Samuel W.

AU - Chau, Thinh

AU - Liu, Hui Xin

AU - Sheng, Lili

AU - Wei, Fang

AU - Stondell, Jesse L

AU - Garcia, Juan Carlos

AU - Du, Yanlei

AU - Bowlus, Christopher

AU - Wan, Yu-Jui Yvonne

PY - 2019/2/1

Y1 - 2019/2/1

N2 - This study investigates the mechanism and consequences of microRNA-22 ( miR-22) induction. Our data revealed for the first time that retinoic acid (RA) and histone deacetylase (HDAC) inhibitors, including short-chain fatty acids and suberanilohydroxamic acid (SAHA), could individually or in combination induce miR-22. This induction was mediated via RA receptor β (RARβ) binding to a direct repeat 5 (DR5) motif. In addition, we uncovered HDAC1 as a novel miR-22 target. In an miR-22-dependent manner, HDAC inhibitors and RA reduced HDAC1, HDAC4, and sirtuin 1 (SIRT1), which were involved in chromatin remodeling of the RARβ and nerve growth factor IB ( NUR77). Thus, HDAC inhibitors and RA-induced miR-22 resulted in simultaneous induction of cytoplasmic RARβ and NUR77, leading to apoptosis of colon cancer cells. In mice, miR-22 and its inducers inhibited the growth of xenograft colon cancer. Moreover, tumor size reduction was accompanied by elevated miR-22, NUR77, and RARβ and by reduced HDACs. In human colon polyps and adenocarcinomas, miR-22 and RARβ were consistently reduced, which was associated with elevated HDAC1, HDAC4, and SIRT1 in colon adenocarcinomas. Results from this study revealed a novel anticancer mechanism of RARβ via miR-22 induction to epigenetically regulate itself and NUR77, providing a promising cancer treatment modality using miR-22 and its inducers.-Hu, Y., French, S. W., Chau, T., Liu, H.-X., Sheng, L., Wei, F., Stondell, J., Garcia, J. C., Du, Y., Bowlus, C. L., Wan, Y.-J. Y. RARβ acts as both an upstream regulator and downstream effector of miR-22, which epigenetically regulates NUR77 to induce apoptosis of colon cancer cells.

AB - This study investigates the mechanism and consequences of microRNA-22 ( miR-22) induction. Our data revealed for the first time that retinoic acid (RA) and histone deacetylase (HDAC) inhibitors, including short-chain fatty acids and suberanilohydroxamic acid (SAHA), could individually or in combination induce miR-22. This induction was mediated via RA receptor β (RARβ) binding to a direct repeat 5 (DR5) motif. In addition, we uncovered HDAC1 as a novel miR-22 target. In an miR-22-dependent manner, HDAC inhibitors and RA reduced HDAC1, HDAC4, and sirtuin 1 (SIRT1), which were involved in chromatin remodeling of the RARβ and nerve growth factor IB ( NUR77). Thus, HDAC inhibitors and RA-induced miR-22 resulted in simultaneous induction of cytoplasmic RARβ and NUR77, leading to apoptosis of colon cancer cells. In mice, miR-22 and its inducers inhibited the growth of xenograft colon cancer. Moreover, tumor size reduction was accompanied by elevated miR-22, NUR77, and RARβ and by reduced HDACs. In human colon polyps and adenocarcinomas, miR-22 and RARβ were consistently reduced, which was associated with elevated HDAC1, HDAC4, and SIRT1 in colon adenocarcinomas. Results from this study revealed a novel anticancer mechanism of RARβ via miR-22 induction to epigenetically regulate itself and NUR77, providing a promising cancer treatment modality using miR-22 and its inducers.-Hu, Y., French, S. W., Chau, T., Liu, H.-X., Sheng, L., Wei, F., Stondell, J., Garcia, J. C., Du, Y., Bowlus, C. L., Wan, Y.-J. Y. RARβ acts as both an upstream regulator and downstream effector of miR-22, which epigenetically regulates NUR77 to induce apoptosis of colon cancer cells.

KW - butyrate

KW - nuclear receptor

KW - propionate

KW - protein deacetylase

KW - short-chain fatty acid

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U2 - 10.1096/fj.201801390R

DO - 10.1096/fj.201801390R

M3 - Article

C2 - 30252536

AN - SCOPUS:85061030025

VL - 33

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JO - FASEB Journal

JF - FASEB Journal

SN - 0892-6638

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