SIRT6 expression is associated with poor prognosis and chemosensitivity in patients with non‐small cell lung cancer

Azuma, Yoko; Yokobori, Takehiko; Mogi, Akira; Altan, Bolag; Yajima, Toshiki; Kosaka, Takayuki; Onozato, Ryoichi; Yamaki, Ei; Asao, Takayuki; Nishiyama, Masahiko; Kuwano, Hiroyuki

doi:10.1002/jso.23975

Cited by 57 publications

(54 citation statements)

References 19 publications

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“…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 . Our study is the first to report that up‐regulation of SIRT6 correlated with clinicopathological features and poor prognosis of OS patients.…”

Section: Discussionsupporting

confidence: 55%

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: Discussionsupporting

confidence: 55%

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

et al. 2017

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“…Cai, et al [31] showed that SIRT6 overexpression can reduce cell proliferation, change the cell distribution of the cell cycle and induce apoptosis via Bcl-2 downregulation and Bax and cleaved caspase-3 upregulation. However, YOKO, et al [32] reported that SIRT6 knockdown did not affect A549 cell proliferation or Bcl-2 expression in this cell line. Similarly, Kim, et al [33] found that cAMP reduces SIRT6 expression to enhance apoptosis via inhibition of the Raf-MEK-ERK pathway.…”

Section: Discussionmentioning

confidence: 91%

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

et al. 2016

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Sirtuin6 (SIRT6), a member of the sirtuins protein family, plays multiple complex roles in cancer. Here, we report that elevated SIRT6 expression was correlated with clinicopathological parameters such as T and N classification in non-small cell lung cancer (NSCLC) patient tumors. SIRT6 overexpression in NSCLC cell lines increased extracellular signal-regulated kinase (p-ERK)1/2 phosphorylation, activated matrix metalloproteinase 9 (MMP9) and promoted tumor cell migration and invasion. Upon treatment with a specific mitogen-activated protein kinase (MEK) 1/2 inhibitor, these effects were abolished. Our results demonstrate SIRT6 upregulation in NSCLC for the first time and suggest a functional role for SIRT6 in promoting migration and invasion through ERK1/2/MMP9 signaling. SIRT6 may serve as a potential therapeutic target in NSCLC and its utility as a prognostic indicator warrants further study.

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“…Expression of Sirt6 has been associated with poor prognosis and chemosensitivity in patients with non-small cell lung, breast, prostate, and skin cancers. 19-22 Sirt6 also plays a role in inflammatory pathways, exerting anti-inflammatory effects at the transcriptional level and in bone metabolism, culminating in low-turnover osteopenia in Sirt6-deficient mice. 23 …”

Section: Introductionmentioning

confidence: 99%

A Chemical Biology Approach to Reveal Sirt6-targeted Histone H3 Sites in Nucleosomes

Wang

Zeng

et al. 2016

ACS Chem. Biol.

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As a member of a highly conserved family of NAD+-dependent histone deacetylases, Sirt6 is a key regulator of mammalian genome stability, metabolism, and life span. Previous studies indicated that Sirt6 is hardwired to remove histone acetylation at H3K9 and H3K56. However, how Sirt6 recognizes its nucleosome substrates has been elusive due to the difficulty of accessing homogenous acetyl-nucleosomes and the low activity of Sirt6 toward peptide substrates. Based on the fact that Sirt6 has an enhanced activity to remove long chain fatty acylation from lysine, we developed an approach to recombinantly synthesize histone H3 with a fatty acylated lysine, Nε-(7-octenoyl)-lysine (OcK), installed at a number of lysine sites and used these acyl-H3 proteins to assemble acyl-nucleosomes as active Sirt6 substrates. A chemical biology approach that visualizes OcK in nucleosomes and therefore allows directly sensitizes Sirt6 activities on its acyl-nucleosome substrates was also formulated. By combining these two approaches, we showed that Sirt6 actively removes acylation from H3K9, H3K18, and H3K27, has relatively low activities toward H3K4 and K3K23, but sluggishly removes acylation at H3K14, H3K36, H3K56, and H3K79. Overexpressing Sirt6 in 293T cells led to downregulated acetylation at H3K18 and K3K27, confirmed these two novel Sirt6-targeted nucleosome lysine sites in cells. Given that downregulation of H3K18 acetylation is correlated with poor prognosis of several cancer types and H3K27 acetylation antagonizes repressive gene regulation by di- and trimethylation at H3K27, our current study implies that Sirt6 may serve as a target for cancer intervention and regulatory pathway investigation in cells.

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SIRT6 expression is associated with poor prognosis and chemosensitivity in patients with non‐small cell lung cancer

Abstract: Our data demonstrated that SIRT6 expression in NSCLC could be a useful prognostic marker and that SIRT6 might represent a novel target gene for predicting sensitivity of chemotherapy in lung adenocarcinoma.

Cited by 57 publications

References 19 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

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

A Chemical Biology Approach to Reveal Sirt6-targeted Histone H3 Sites in Nucleosomes

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