SIRT1 promotes epithelial–mesenchymal transition and metastasis in colorectal cancer by regulating Fra-1 expression

Cheng, Feifei; Su, Li; Yao, Chao; Liu, Limei; Shen, Junjie; Liu, Chungang; Chen, Xuejiao; Luo, Yongli; Jiang, Lupin; Shan, Juanjuan; Chen, Jun; Zhu, Wei; Shao, Jimin; Qian, Cheng

doi:10.1016/j.canlet.2016.03.010

Cited by 77 publications

(48 citation statements)

References 38 publications

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“…32, 33 Thus, SIRT1 executes its senescence regulation by inhibiting the p53/p21 pathway and subsequently promoting tumorgenesis. 34 Cheng et al 35 reported that SIRT1 is highly expressed in CRC and inversely correlated with CRC prognosis, indicating that SIRT1 is a novel oncogene that induces CRC tumorigenesis. As expected, BRG1 KD upregulated the expression of K382-acetylated p53.…”

Section: Discussionmentioning

confidence: 99%

Loss of BRG1 induces CRC cell senescence by regulating p53/p21 pathway

Wang

et al. 2017

Cell Death Dis

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Brahma-related gene-1 (BRG1) is the specific ATPase of switch/sucrose nonfermentable chromatin-remodeling complex that is aberrantly expressed or mutated in various cancers. However, the exact role of BRG1 in oncogenesis remains unknown. In this study, we demonstrate that the knockdown (KD) of BRG1 promotes cellular senescence by influencing the SIRT1/p53/p21 signal axis in colorectal cancer (CRC). In particular, we reveal that the expression level of BRG1 is inversely correlated with p21, one of the classic senescence regulators, and is decreased in senescent CRC cells. KD of BRG1 promoting senescence is indicated by the increase of senescence-associated β-galactosidase (SA-β-gal) activity, inhibition of cell proliferation, induction of cell cycle arrest, and formation of senescence-associated heterochromatin foci. BRG1 binds to SIRT1 and interferes with SIRT1-mediated deacetylation of p53 at K382. Rescue experiments by co-silencing p53 or treatment with EX527, a SIRT1-specific inhibitor, abrogated the cellular senescence induced by KD of BRG1. BRG1 KD cells resulted in smaller tumor formation than that in control cells in vivo. Collectively, our study shows that BRG1 has an important role in cellular senescence and tumor growth. The BRG1/SIRT1/p53 signal axis is a novel mechanism of cell senescence in CRC and is a new potential target for cancer therapy.

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Section: Discussionmentioning

confidence: 99%

Loss of BRG1 induces CRC cell senescence by regulating p53/p21 pathway

Wang

et al. 2017

Cell Death Dis

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“…46 FRA-1 not only controls expression of genes involved in cell motility, epithelial-to-mesenchymal transition 13, 45, 47, 48 and cell invasion, 15, 17, 32, 49 but it also controls proliferation, 15, 50, 51 metastatic outgrowth 44 and the stem cell phenotype of cancer cells. 52 Several FRA-1-regulated genes 15, 17, 32, 49 have been demonstrated to facilitate cancer cell invasion including MMP-1, MMP-2 and MMP-9.…”

Section: Discussionmentioning

confidence: 99%

MLK3 regulates FRA-1 and MMPs to drive invasion and transendothelial migration in triple-negative breast cancer cells

et al. 2017

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Mixed-lineage kinase 3 (MLK3), a mitogen-activated protein kinase kinase kinase (MAP3K), has critical roles in metastasis of triple-negative breast cancer (TNBC), in part by regulating paxillin phosphorylation and focal adhesion turnover. However the mechanisms and the distinct step(s) of the metastatic processes through which MLK3 exerts its influence are not fully understood. Here we report that in non-metastatic, estrogen receptor-positive breast cancer (ER+ BC) cells, induced MLK3 expression robustly upregulates the oncogenic transcription factor, FOS-related antigen-1 (FRA-1), which is accompanied by elevation of matrix metalloproteinases (MMPs), MMP-1 and MMP-9. MLK3-induced ER+ BC cell invasion is abrogated by FRA-1 silencing, demonstrating that MLK3 drives invasion through FRA-1. Conversely, in metastatic TNBC models, high FRA-1 levels are significantly reduced upon depletion of MLK3 by either gene silencing or by the CRISPR/Cas9n editing approach. Furthermore, ablation of MLK3 or MLK inhibitor treatment decreases expression of both MMP-1 and MMP-9. Consistent with the role of tumor cell-derived MMP-1 in endothelial permeability and transendothelial migration, both of these are reduced in MLK3-depleted TNBC cells. In addition, MLK inhibitor treatment or MLK3 depletion, which downregulates MMP-9 expression, renders TNBC cells defective in Matrigel invasion. Furthermore, circulating tumor cells derived from TNBC-bearing mice display increased levels of FRA-1 and MMP-1 compared with parental cells, supporting a role for the MLK3–FRA-1–MMP-1 signaling axis in vascular intravasation. Our results demonstrating the requirement for MLK3 in controlling the FRA-1/MMPs axis suggest that MLK3 is a promising therapeutic target for treatment of TNBC.

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“…The transfected cells were seeded in 6-well plates at the density of 8×10 4 . A sterile tip was employed to draw lines in the hole, and hardly any cells grew within the crossed places.…”

Section: Scratch Experimentsmentioning

confidence: 99%

The Effect of LncRNA H19/miR-194-5p Axis on the Epithelial-Mesenchymal Transition of Colorectal Adenocarcinoma

Chang-feng

Wang³

et al. 2018

Cell Physiol Biochem

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Background/Aims: Since the combined actions of lncRNAs and miRNAs have been considered to be involved in the occurrence and development of various neoplasms, the main purpose of this study was to discover whether and how lncRNA H19 and miR-194 influenced the epithelial-mesenchymal transition (EMT) process of colorectal adenocarcinoma (CRA). Methods: Totally 214 pairs of CRA and adjacent normal tissues were collected, and 5 human CRA cell lines (i.e. HCT116, HT-29, RKO SW280 and Lovo) were purchased. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was adopted to quantify the H19 and miR-194-5p expressions in cells and tissues. The expressions of FoxM1, E-cadherin, vimentin, N-cadherin were determined using western blot. On the side, si-H19, si-NC, miR-194-5p mimic, miR-194-5p inhibitor and negative control (NC) were transfected into CRA cell lines. Meanwhile, the invasive, migratory and proliferative conditions of the cells were assessed through transwell, wound healing and colony-forming experiments, with final verification of the relationship between H19 and miR-194-5p employing dual-luciferase reporter gene assay. Results: Highly-expressed H19, lowly-expressed miR-194-5p, low-grade differentiation and lymph node metastasis appeared as the independent predictors of unfavorable prognosis in CRA patients’ (all P< 0.05). It indicated that FoxM1 expression displayed positive correlations with H19 expression, yet negative associations with miR-194-5p expression within CRA tissues (P< 0.05). In addition, transfection of H19-siRNA and miR-145-5p mimic triggered a conspicuous increase in E-cadherin expression, as well as an evidently down-regulation in vimentin and N-cadherin expressions within HT29 and RKO cells (P< 0.05). On the other hand, the invasive and migratory capacities of CRA cells were significantly hindered (P< 0.05). Moreover, the luciferase reporter gene assay confirmed that H19 modified miR-194-5p expression through directly targeting at it (P< 0.05). Ultimately, FoxM1 could reverse the role of miR-194-5p in inhibiting invasion, migration and EMT of CRA cells (P< 0.05). Conclusion: LncRNA H19/miR-194/FoxM1 axis could serve as a profound target for the diagnosis and treatment of CRA.

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SIRT1 promotes epithelial–mesenchymal transition and metastasis in colorectal cancer by regulating Fra-1 expression

Cited by 77 publications

References 38 publications

Loss of BRG1 induces CRC cell senescence by regulating p53/p21 pathway

Loss of BRG1 induces CRC cell senescence by regulating p53/p21 pathway

MLK3 regulates FRA-1 and MMPs to drive invasion and transendothelial migration in triple-negative breast cancer cells

The Effect of LncRNA H19/miR-194-5p Axis on the Epithelial-Mesenchymal Transition of Colorectal Adenocarcinoma

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