title: SIRT1 directly regulates SOX2 to maintain self-renewal and multipotency in bone marrow-derived mesenchymal stem cells.
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.
authors.affiliation: Department of Orthopaedic Surgery, Yonsei University College of Medicine, Seoul, South Korea; Brain Korea 21 PLUS Project for Medical Science, Yonsei University, Seoul, South Korea.
authors.forename: Dong Suk
authors.initials: DS
authors.lastname: Yoon
authors.forename: Yoorim
authors.initials: Y
authors.lastname: Choi
authors.forename: Yeonsue
authors.initials: Y
authors.lastname: Jang
authors.forename: Moses
authors.initials: M
authors.lastname: Lee
authors.forename: Woo Jin
authors.initials: WJ
authors.lastname: Choi
authors.forename: Sung-Hwan
authors.initials: SH
authors.lastname: Kim
authors.forename: Jin Woo
authors.initials: JW
authors.lastname: Lee
mesh_terms: D000328:Adult; D001853:Bone Marrow / Q000378:metabolism*; D001854:Bone Marrow Cells / Q000166:cytology* / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology*; D049109:Cell Proliferation / Q000502:physiology; D000066673:Cell Self Renewal; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000502:physiology; D034622:RNA Interference / Q000502:physiology; D055748:SOXB1 Transcription Factors / Q000378:metabolism*; D056564:Sirtuin 1 / Q000378:metabolism*
chemical_list: C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors; C447939:SIRT1 protein, human; D056564:Sirtuin 1
keywords: Acetylation; Bone marrow-mesenchymal stem cells; Multipotency; SIRT1; SOX2; Self-renewal