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SCF increases cardiac stem cell migration through PI3K/AKT and MMP‑2/‑9 signaling.

ABSTRACT: The transplantation of cardiac stem cells (CSCs) is thought to be responsible for improving the performance of injured heart induced by myocardial infarction (MI). However, the mechanisms involved in the migration of activated CSCs post‑MI remain to be clarified. In this study, CSCs were isolated from rat hearts and a cellular migration assay was performed using a 24‑well Transwell system. Stem cell factor (SCF) induced CSC migration in a concentration‑dependent manner, which could be blocked with an SCF antibody as well as a PI3K/AKT inhibitor, LY294002. Moreover, SCF induced the expression and activity of matrix metalloproteinase (MMP)‑2 and MMP‑9 in a concentration‑ and time‑dependent manner, as measured by quantitative RT‑PCR, western blot analysis and gelatin zymography. Results of western blot analysis revealed phosphorylated AKT was markedly increased in SCF‑treated CSCs and that inhibition of SCF/c‑Kit signaling or phospho‑AKT activity significantly attenuated the SCF‑induced expression of MMP‑2 and MMP‑9. Thus, our results showed that SCF partially mediated CSC migration via the activation of PI3K/AKT/MMP‑2/‑9 signaling.

SUBMITTER: Guo J

PROVIDER: S-EPMC4072340 | biostudies-literature |

REPOSITORIES: biostudies-literature

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miR-21 increases c-kit<sup>+</sup> cardiac stem cell proliferation <i>in vitro</i> through PTEN/PI3K/Akt signaling.

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Project description:Lysine acetyltransferase KAT6A is a chromatin regulator that contributes to histone modification and cancer, but the basis of its actions are not well understood. Here, we identify a KAT6A signaling pathway that facilitates glioblastoma (GBM), where it is upregulated. KAT6A expression was associated with GBM patient survival. KAT6A silencing suppressed cell proliferation, cell migration, colony formation, and tumor development in an orthotopic mouse xenograft model system. Mechanistic investigations demonstrated that KAT6A acetylates lysine 23 of histone H3 (H3K23), which recruits the nuclear receptor binding protein TRIM24 to activate PIK3CA transcription, thereby enhancing PI3K/AKT signaling and tumorigenesis. Overexpressing activated AKT or PIK3CA rescued the growth inhibition due to KAT6A silencing. Conversely, the pan-PI3K inhibitor LY294002 abrogated the growth-promoting effect of KAT6A. Overexpression of KAT6A or TRIM24, but not KAT6A acetyltransferase activity-deficient mutants or TRIM24 mutants lacking H3K23ac-binding sites, promoted PIK3CA expression, AKT phosphorylation, and cell proliferation. Taken together, our results define an essential role of KAT6A in glioma formation, rationalizing its candidacy as a therapeutic target for GBM treatment. Cancer Res; 77(22); 6190-201. ©2017 AACR.

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