Distant metastasis is the main cause of breast cancer-related death; however, effective therapeutic strategies targeting metastasis are still scarce. This is largely attributable to the spatiotemporal intratumor heterogeneity during metastasis. Here we show that protein deacetylase SIRT7 is significantly downregulated in breast cancer lung metastases in human and mice, and predicts metastasis-free survival. SIRT7 deficiency promotes breast cancer cell metastasis, while temporal expression of Sirt7 inhibits metastasis in polyomavirus middle T antigen breast cancer model. Mechanistically, SIRT7 deacetylates and promotes SMAD4 degradation mediated by β-TrCP1, and SIRT7 deficiency activates transforming growth factor-β signaling and enhances epithelial-to-mesenchymal transition. Significantly, resveratrol activates SIRT7 deacetylase activity, inhibits breast cancer lung metastases, and increases survival. Our data highlight SIRT7 as a modulator of transforming growth factor-β signaling and suppressor of breast cancer metastasis, meanwhile providing an effective anti-metastatic therapeutic strategy.

Bone marrow mesenchymal stem cells (MSCs) have the potential to migrate to the site of injury and regulate the repair process. Aquaporin 1 (Aqp1) is a water channel molecule and a regulator of endothelial cell migration. To study the role of Apq1 in MSC migration, we manipulated the expression of the Aqp1 gene in MSCs and explored its effects on MSC migration both in vitro and in vivo. Overexpression of Aqp1 promoted MSC migration, while depletion of Aqp1 impaired MSC migration in vitro. When the green fluorescent protein (GFP) labeled Aqp1 overexpressing MSCs were systemically injected into rats with a femoral fracture, there were significantly more GFP-MSCs found at the fracture gap in the Aqp1-GFP-MSC-treated group compared to the GFP-MSC group. To elucidate the underlying mechanism, we screened several migration-related regulators. The results showed that b-catenin and focal adhesion kinase (FAK) were upregulated in the Aqp1-MSCs and downregulated in the Aqp1-depleted MSCs, while C-X-C chemokine receptor type 4 had no change. Furthermore, b-catenin and FAK were co-immunoprecipitated with Aqp1, and depletion of FAK abolished the Aqp1 effects on MSC migration. This study demonstrates that Aqp1 enhances MSC migration ability mainly through the FAK pathway and partially through the b-catenin pathway. Our finding suggests a novel function of Aqp1 in governing MSC migration, and this may aid MSC therapeutic applications.

Cancer stem cell (CSC)-dictated intratumor heterogeneity accounts for the majority of drug-resistance and distant metastases of breast cancers. Here, we identify a SIRT1-PRRX1-KLF4-ALDH1 circuitry, which couples CSCs, chemo-resistance, metastasis and aging. Pro-longevity protein SIRT1 deacetylates and stabilizes the epithelial-to-mesenchymal-transition (EMT) inducer PRRX1, which inhibits the transcription of core stemness factor KLF4. Loss of SIRT1 destabilizes PRRX1, disinhibits KLF4, and activates the transcription of ALDH1, which induces and functionally marks CSCs, resulting in chemo-resistance and metastatic relapse. Clinically, the level of PRRX1 is positively linked to SIRT1, whereas KLF4 is reversely correlated. Importantly, KLF4 inhibitor Kenpaullone sensitizes breast cancer cells and xenograft tumors to Paclitaxel and improves therapeutic effects. Our findings delineate a SIRT1-centered circuitry that regulates CSC origination, and targeting this pathway might be a promising therapeutic strategy.

Mesenchymal stem cells (MSCs) are a promising cell resource for tissue engineering. Sry-related high-mobility group box 11 (Sox11) plays critical roles in neural development and organogenesis. In the present study, we investigated the role of Sox11 in regulating trilineage differentiation (osteogenesis, adipogenesis, and chondrogenesis) and migration of MSCs, and explored the effect of systemically administrated Sox11-modified MSCs on bone fracture healing using the rat model of open femur fracture. Our results demonstrated that Sox11 overexpression increased the trilineage differentiation and migration of MSCs, as well as cell viability under oxidative stress. The effect of Sox11 on osteogenesis was confirmed by ectopic bone formation assay conducted in nude mice. In addition, we found that Sox11 could activate the bone morphogenetic protein (BMP)/Smad signaling pathway in MSCs. By dual-luciferase reporter assay, we also demonstrated that Sox11 could transcriptionally activate runtrelated transcription factor 2 (Runx2) and CXC chemokine receptor-4 (CXCR4) expression. The activation of the BMP/Smad signaling pathway and Runx2, CXCR4 expression may have a synergic effect, which largely contributed to the effect of Sox11 on MSC fate determination and migration. Finally, using an open femur fracture model in rats, we found that a larger number of MSCs stably expressing Sox11 migrated to the fracture site and improved bone fracture healing. Taken together, our study shows that Sox11 is an important regulator of MSC differentiation and migration, and Sox11-modified MSCs may have clinical implication for accelerating bone fracture healing, which can reduce the delayed unions or non-