SIRT1 directly regulates SOX2 to maintain self-renewal and multipotency in bone marrow-derived mesenchymal stem cells

Dong Suk Yoon, Yoorim Choi, Yeonsue Jang, Moses Lee, Woo Jin Choi, Sung Hwan Kim, jinwoo lee

Research output: Contribution to journalArticle

49 Citations (Scopus)

Abstract

SOX2 is crucial for the maintenance of the self-renewal capacity and multipotency of mesenchymal stem cells (MSCs); however, the mechanism by which SOX2 is regulated remains unclear. Here, we report that RNA interference of sirtuin 1 (SIRT1) in human bone marrow (BM)-derived MSCs leads to a decrease of SOX2 protein, resulting in the deterioration of the self-renewal and differentiation capacities of BM-MSCs. Using immunoprecipitation, we demonstrated direct binding between SIRT1 and SOX2 in HeLa cells overexpressing SOX2. We further discovered that the RNA interference of SIRT1 induces the acetylation, nuclear export, and ubiquitination of SOX2, leading to proteasomal degradation in BM-MSCs. SOX2 suppression by trichostatin A (TSA), a known histone deacetylase inhibitor, was reverted by treatment with resveratrol (0.1 and 1 μM), a known activator of SIRT1 in BM-MSCs. Furthermore, 0.1 and 1 μM resveratrol reduced TSA-mediated acetylation and ubiquitination of SOX2 in BM-MSCs. SIRT1 activation by resveratrol enhanced the colony-forming ability and differentiation potential to osteogenic and adipogenic lineages in a dose-dependent manner. However, the enhancement of self-renewal and multipotency by resveratrol was significantly decreased to basal levels by RNA interference of SOX2. These results strongly suggest that the SIRT1-SOX2 axis plays an important role in maintaining the self-renewal capability and multipotency of BM-MSCs. In conclusion, our findings provide evidence for positive SOX2 regulation by post-translational modification in BM-MSCs through the inhibition of nuclear export and subsequent ubiquitination, and demonstrate that SIRT1-mediated deacetylation contributes to maintaining SOX2 protein in the nucleus. Stem Cells 2014;32:3219-3231

Original languageEnglish
Pages (from-to)3219-3231
Number of pages13
JournalStem Cells
Volume32
Issue number12
DOIs
Publication statusPublished - 2014 Dec 1

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Sirtuin 1
Mesenchymal Stromal Cells
Bone Marrow
Ubiquitination
trichostatin A
RNA Interference
Cell Nucleus Active Transport
Acetylation
Histone Deacetylase Inhibitors
Post Translational Protein Processing
HeLa Cells
Immunoprecipitation
Proteins
Stem Cells

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Developmental Biology
  • Cell Biology

Cite this

Yoon, Dong Suk ; Choi, Yoorim ; Jang, Yeonsue ; Lee, Moses ; Choi, Woo Jin ; Kim, Sung Hwan ; lee, jinwoo. / SIRT1 directly regulates SOX2 to maintain self-renewal and multipotency in bone marrow-derived mesenchymal stem cells. In: Stem Cells. 2014 ; Vol. 32, No. 12. pp. 3219-3231.
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abstract = "SOX2 is crucial for the maintenance of the self-renewal capacity and multipotency of mesenchymal stem cells (MSCs); however, the mechanism by which SOX2 is regulated remains unclear. Here, we report that RNA interference of sirtuin 1 (SIRT1) in human bone marrow (BM)-derived MSCs leads to a decrease of SOX2 protein, resulting in the deterioration of the self-renewal and differentiation capacities of BM-MSCs. Using immunoprecipitation, we demonstrated direct binding between SIRT1 and SOX2 in HeLa cells overexpressing SOX2. We further discovered that the RNA interference of SIRT1 induces the acetylation, nuclear export, and ubiquitination of SOX2, leading to proteasomal degradation in BM-MSCs. SOX2 suppression by trichostatin A (TSA), a known histone deacetylase inhibitor, was reverted by treatment with resveratrol (0.1 and 1 μM), a known activator of SIRT1 in BM-MSCs. Furthermore, 0.1 and 1 μM resveratrol reduced TSA-mediated acetylation and ubiquitination of SOX2 in BM-MSCs. SIRT1 activation by resveratrol enhanced the colony-forming ability and differentiation potential to osteogenic and adipogenic lineages in a dose-dependent manner. However, the enhancement of self-renewal and multipotency by resveratrol was significantly decreased to basal levels by RNA interference of SOX2. These results strongly suggest that the SIRT1-SOX2 axis plays an important role in maintaining the self-renewal capability and multipotency of BM-MSCs. In conclusion, our findings provide evidence for positive SOX2 regulation by post-translational modification in BM-MSCs through the inhibition of nuclear export and subsequent ubiquitination, and demonstrate that SIRT1-mediated deacetylation contributes to maintaining SOX2 protein in the nucleus. Stem Cells 2014;32:3219-3231",
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SIRT1 directly regulates SOX2 to maintain self-renewal and multipotency in bone marrow-derived mesenchymal stem cells. / Yoon, Dong Suk; Choi, Yoorim; Jang, Yeonsue; Lee, Moses; Choi, Woo Jin; Kim, Sung Hwan; lee, jinwoo.

In: Stem Cells, Vol. 32, No. 12, 01.12.2014, p. 3219-3231.

Research output: Contribution to journalArticle

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