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 language | English (US) |
|---|---|
| Pages (from-to) | 2314-2326 |
| Number of pages | 13 |
| Journal | FASEB journal : official publication of the Federation of American Societies for Experimental Biology |
| Volume | 33 |
| Issue number | 2 |
| DOIs | |
| State | Published - Feb 1 2019 |
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Keywords
- butyrate
- nuclear receptor
- propionate
- protein deacetylase
- short-chain fatty acid
ASJC Scopus subject areas
- Biotechnology
- Biochemistry
- Molecular Biology
- Genetics
Cite this
RARβ acts as both an upstream regulator and downstream effector of miR-22, which epigenetically regulates NUR77 to induce apoptosis of colon cancer cells. / Hu, Ying; French, Samuel W.; Chau, Thinh; Liu, Hui Xin; Sheng, Lili; Wei, Fang; Stondell, Jesse L; Garcia, Juan Carlos; Du, Yanlei; Bowlus, Christopher; Wan, Yu-Jui Yvonne.
In: FASEB journal : official publication of the Federation of American Societies for Experimental Biology, Vol. 33, No. 2, 01.02.2019, p. 2314-2326.Research output: Contribution to journal › Article
}
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
UR - http://www.scopus.com/inward/record.url?scp=85061030025&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85061030025&partnerID=8YFLogxK
U2 - 10.1096/fj.201801390R
DO - 10.1096/fj.201801390R
M3 - Article
C2 - 30252536
AN - SCOPUS:85061030025
VL - 33
SP - 2314
EP - 2326
JO - FASEB Journal
JF - FASEB Journal
SN - 0892-6638
IS - 2
ER -