Upregulation of SIRT6 predicts poor prognosis and promotes metastasis of non-small cell lung cancer via the ERK1/2/MMP9 pathway

Bai, Lihong; Lin, Guoli; Sun, Lili; Liu, Yangli; Huang, Xinyan; Cao, Chuang-Jie; Guo, Yubiao; Xie, Canmao

doi:10.18632/oncotarget.9750

Cited by 76 publications

(75 citation statements)

References 44 publications

(54 reference statements)

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“…Sirtuin 6 is selectively down-regulated in several human cancers [11]. On the other hand, overexpression of SIRT6 is observed in HCC and NSCLC [15,21]. This evidence supports conflicting expressions for SIRT6 in cancer.…”

Section: Discussionmentioning

confidence: 77%

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Retracted: Sirtuin 6 contributes to migration and invasion of osteosarcoma cells via the ERK1/2/MMP9 pathway

et al. 2017

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Dysregulation of sirtuin 6 (SIRT6) is actively involved in tumor progression. High levels of SIRT6 have been associated with hepatocellular carcinoma and non‐small cell lung cancer, and SIRT6 facilitates growth and metastasis of cancer cells. However, the clinical significance and biological function of SIRT6 are not known for osteosarcoma (OS). Here, we report that SIRT6 was notably overexpressed in OS tissues compared with non‐cancerous specimens. The high level of SIRT6 was prominently correlated with malignant clinical parameters and poor prognosis of OS patients. SIRT6 was also up‐regulated in OS cells. SIRT6 knockdown inhibited the invasion and migration of Saos‐2 and U2OS cells in vitro , while SIRT6 restoration increased these cellular biological behaviors in MG‐63 cells. Mechanistically, SIRT6 up‐regulated expression of matrix metallopeptidase 9 (MMP9) in OS cells. MMP9 restoration partially abolished the effects of SIRT6 knockdown on OS cells, with increased cell migration and invasion. MMP9 knockdown reduced migration and invasion of SIRT6‐overexpressing MG‐63 cells. Furthermore, SIRT6 positively modulated the levels of phosphorylated extracellular signal‐regulated kinases 1 and 2 (ERK1/2). PD098059 and PD0325901, inhibitors of mitogen‐activated protein kinase kinase (MEK), blocked the regulatory effects of SIRT6 on p‐ERK1/2 and MMP9 levels, suggesting that SIRT6 regulated MMP9 abundance probably through the MEK–ERK1/2 pathway. These results suggest that SIRT6 may act as a prognostic predictor and a drug target for OS patients.

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Section: Discussionmentioning

confidence: 77%

“…Up‐regulation of SIRT6 was highly associated with shorter survival in HCC . A recent study showed that high SIRT6‐expressing NSCLC patients have a lower cumulative survival rate as compared with low SIRT6‐expressing patients . Moreover, the subcellular localization of SIRT6 is associated with poor prognosis of patients with NSCLC .…”

Section: Discussionmentioning

confidence: 99%

Retracted: Sirtuin 6 contributes to migration and invasion of osteosarcoma cells via the ERK1/2/MMP9 pathway

et al. 2017

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“…SIRT6 copy number is increased in some hematopoietic cancer cell lines [5]. Moreover, elevated SIRT6 expression occurs in cases of Multiple Myeloma (MM) and some solid tumors, and in some instances is associated with poor clinical outcome [47-52]. Thus, SIRT6 could have oncogenic rather than tumor suppressive functions in certain contexts.…”

Section: Mechanisms Of Tumor Suppression and Regulation Of Cancer Promentioning

confidence: 99%

SIRT6: Novel Mechanisms and Links to Aging and Disease

Tasselli

Zheng

Chua

2017

Trends in Endocrinology & Metabolism

213

196

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SIRT6, a member of the Sirtuin family of NAD+-dependent enzymes, has established roles in chromatin signaling and genome maintenance. Through these functions, SIRT6 protects against aging-associated pathologies including metabolic disease and cancer, and can promote longevity in mice. Research from the last few years has revealed that SIRT6 is a complex enzyme with multiple substrates and catalytic activities, and uncovered novel SIRT6 functions in maintenance of organismal health span. Here, we review these new discoveries and models of SIRT6 biology in four areas: heterochromatin stabilization and silencing, stem cell biology, cancer initiation and progression, and regulation of metabolic homeostasis. We discuss possible implications of these findings for therapeutic interventions in aging and aging-related disease processes.

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“…Metastasis is closely associated with the prognosis and recurrence of cancer (15,16). To confirm the effects of isofraxidin on cell motility, Transwell migration and invasion assays were conducted.…”

Section: Isofraxidin Suppresses the Migration And Invasion Of A549 Cementioning

confidence: 99%

Anticancer effects of isofraxidin against A549 human lung cancer cells via the EGFR signaling pathway

et al. 2018

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Lung cancer is the leading cause of mortality due to tumor malignancy worldwide. In recent years, the treatment of lung cancer with chemotherapy has demonstrated notable resistance and insensitivity. Therefore, it is of great importance to investigate anti‑lung cancer drugs with high efficiency and low toxicity. In the present study, the effects of isofraxidin on lung cancer cells and the associated mechanisms were investigated. The results revealed that, in vivo and in vitro, isofraxidin exhibited marked inhibitory effects on the A549 lung cancer cell line. The results of Cell Counting kit‑8, Transwell migration and Matrigel invasion assays, and flow cytometry to determine apoptosis, revealed that isofraxidin significantly inhibited the proliferation, migration and invasion of A549 cells, and induced the cell apoptosis. Furthermore, western blot analysis demonstrated that isofraxidin treatment led to effects on the expression of apoptosis‑associated proteins, including members of the Bcl‑2 protein family, and invasion‑associated proteins, including matrix metallopeptidase (MMP)‑2 and MMP‑9, which may occur via inhibition of the expression of phosphorylated (p)‑epidermal growth factor receptor, p‑AKT and p‑extracellular signal‑regulated kinase. This regulation of protein expression may contribute to the inhibition of proliferation, migration and invasion of A549lung cancer cells by isofraxidin. In addition, despite the inhibitory effects on the A549 lung cancer cell line, the present study revealed that isofraxidin exhibited low toxicity towards BEAS‑2B normal lung epithelial cells within a certain dose range (0‑160 µM), indicating that isofraxidin may be employed for lung cancer treatment with hypotoxicity and fewer side effects. In conclusion, isofraxidin may be a novel candidate for anti‑lung cancer chemotherapy.

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Upregulation of SIRT6 predicts poor prognosis and promotes metastasis of non-small cell lung cancer via the ERK1/2/MMP9 pathway

Cited by 76 publications

References 44 publications

Retracted: Sirtuin 6 contributes to migration and invasion of osteosarcoma cells via the ERK1/2/MMP9 pathway

Retracted: Sirtuin 6 contributes to migration and invasion of osteosarcoma cells via the ERK1/2/MMP9 pathway

SIRT6: Novel Mechanisms and Links to Aging and Disease

Anticancer effects of isofraxidin against A549 human lung cancer cells via the EGFR signaling pathway

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