SIRT6 Depletion Suppresses Tumor Growth by Promoting Cellular Senescence Induced by DNA Damage in HCC

Lee, Namgyu; Ryu, Hye Guk; Kwon, Jung‐Hee; Kim, Dae-Kyum; Kim, Sae Rom; Wang, Hee Jung; Kim, Kyong‐Tai; Choi, Kwan Yong

doi:10.1371/journal.pone.0165835

Cited by 36 publications

(31 citation statements)

References 42 publications

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“…Furthermore, SIRT6 was underexpressed and was negatively correlated with miR-33a expression in the glioma specimens. In contrast, upregulation of SIRT6 was reported in NSCLC and HCC (30,31), which was consistent with the downregulation of miR-33a in these cancers (9,12). All these data suggest an inverse correlation between miR-33a and SIRT6 expression.…”

Section: Discussionsupporting

confidence: 79%

Suppression of SIRT6 by miR-33a facilitates tumor growth of glioma through apoptosis and oxidative stress resistance

Chang

Lin²,

et al. 2017

Oncology Reports

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microRNA-33a (miR-33a) belongs to the miR-33 family that is implicated in the progression of various types of cancers. Aberrant expression of miR-33a has been detected in several human cancers, and has been shown to regulate the migration and invasion as well as proliferation and apoptosis of tumor cells. However, the clinical significance and precise mechanisms underlying the dysfunction of miR-33a in glioma have not been well investigated in previous studies. In this study, overexpression of miR-33a was observed in clinical glioma specimens and cell lines. Clinicopathological detection revealed that miR-33a highly expressing patients showed large tumor sized and advanced World Health Organization (WHO) grade as well as reduced overall survival. Furthermore, the results of in vitro experiments confirmed that loss of miR-33a resulted in reduced proliferation and enhanced apoptosis in U251 cells, while miR-33a restoration showed opposite effects in U87 cells. Further studies indicated that miR-33a knockdown restrained tumor growth of glioma in vivo. miR-33a negatively regulated the expression of sirtuin 6 (SIRT6) at both mRNA and protein levels via targeting the 3'UTR of SIRT6 mRNA. SIRT6 was underexpressed and inversely correlated with miR-33a expression in the glioma tissues. Mechanistically, SIRT6 overexpression increased the levels of lactate dehydrogenase (LDH) and reactive oxygen species (ROS) while it reduced cell survival under H2O2 treatment. In addition, SIRT6 restoration led to apoptosis with alterative expression of Bax, Bcl-2, cleaved caspase-8, and inhibition of Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) pathway in glioma. Thus, our studies demonstrated that the deregulation of miR-33a may promote tumor development in human glioma by regulating the expression of its target gene, SIRT6.

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Section: Discussionsupporting

confidence: 79%

Suppression of SIRT6 by miR-33a facilitates tumor growth of glioma through apoptosis and oxidative stress resistance

Chang

Lin²,

et al. 2017

Oncology Reports

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“…But Marquardt et al reported that overexpression of SIRT6 did not lead to a change in cell proliferation [ 12 ]. On the contrary, Lee et al reported that SIRT6 knockdown by shRNA suppressed the growth of HCC cells (Huh7, SNU475 and SNU449) [ 17 ]. Ran et al reported that depletion of SIRT6 inhibited the growth of liver cancer cell lines (PLC/PRF/5, SMMC-7721, Huh-7 and SK-Hep-1) [ 18 ].…”

Section: Discussionmentioning

confidence: 99%

“…However, other two studies reported opposite results. Lee et al reported that SIRT6 depletion reduced colony formation of HCC cells in soft agar and tumor growth in xenograft mouse model [ 17 ]. Feng et al reported that upregulation of SIRT6 was required for TGF-β1/H 2 O 2 /HOCl to promote the tumorigenicity of HCC cells owing to that suppression of SIRT6 expression could abrogate the promoting effects of TGF-β1/H 2 O 2 /HOCl on the tumorigenicity of HCC cells [ 23 ].…”

Section: Discussionmentioning

confidence: 99%

“…Zhang et al reported that overexpression of SIRT6 suppressed HCC cell proliferation and induced apoptosis [ 16 ]. Additional two studies [ 17 , 18 ] suggested that SIRT6 acted as an oncogene in HCC development. Their results showed that SIRT6 was upregulated in a subset of HCC tissues and SIRT6 knockdown by shRNA suppressed the growth of HCC cells, induced apoptosis, and inhibited tumor growth of HCC cells in vivo .…”

Section: Introductionmentioning

confidence: 99%

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Overexpression of SIRT6 attenuates the tumorigenicity of hepatocellular carcinoma cells

Wang

Pan

et al. 2017

Oncotarget

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ObjectiveThis study aimed to explore the effects of overexpression of sirtuin 6 (SIRT6) on the tumorigenicity of hepatocellular carcinoma (HCC) cellsMethodsStable SIRT6-overexpressed HCC cell lines were established by transfecting SIRT6 plasmid. Soft agar assay and tumor xenograft assay in nude mice were applied. Flow cytometry was employed to detect cell cycle distribution. Western blotting analysis was used to detect the expression of proteins.ResultsOverexpression of SIRT6 attenuated HepG2 and HCCLM3 cells proliferation, colony formation in vitro and tumor formation in nude mice, and resulted in the G1 phase cell cycle arrest. Overexpression of SIRT6 reduced the expression of cyclin D1 and p-ERK proteins in both HepG2 and HCCLM3 cells.ConclusionOverexpression of SIRT6 attenuates the tumorigenicity of HCC cells.

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“…Bromodeoxyuridine (BrdU) incorporation assays were conducted as described previously (Lee et al, 2016). After overnight starvation, the infected or/and transfected cells were pulsed with 10 mM BrdU (Sigma, St Louis, Mo, USA) for 10 h. The cells were then fixed in 4% paraformaldehyde and treated with 2 M HCl containing 1% Triton X-100.…”

Section: Brdu Incorporation Assaysmentioning

confidence: 99%

RGNNV-induced cell cycle arrest at G1/S phase enhanced viral replication via p53-dependent pathway in GS cells

et al. 2018

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Nervous necrosis virus (NNV) is a ubiquitous pathogen in the aquaculture worldwide. Little is known about the relationship between NNV virus and host cells. Our studies showed that RGNNV infection could induce cell cycle arrest via activation of p53 signaling in cultured host cells. Infection of RGNNV redistributed NPM1, stabilized p53 and inhibited cell proliferation by inducing G1 arrest. RGNNV infection also led to phosphorylation and accumulation of p53 in a time-dependent manner. Furthermore, RGNNV infection upregulated cyclin-dependent kinase inhibitor 1 A (p21) and downregulated cyclin E and cyclin-dependent kinase 2 (CDK2). The expression of genes in the p53 pathway did not change significantly after p53 knockdown by pifithrin-α during RGNNV infection. However, NPM1 knockdown could abrogate RGNNV-induced cell proliferation inhibition, activation of p53 signaling and cell cycle arrest. In addition, RGNNV infection of the cells synchronized in various stages of cell cycle showed that viral genomic RNA and virus titer were higher in the cells released from G1 phase- or S phase-synchronized cells than that in the cells released from the G2 phase-synchronized or asynchronous cells after 18 h p.i. Therefore, our study reveals that RGNNV infection induces the p53-dependent pathway, resulting in a cell cycle arrest at G1 phase in host cells, which might provide a favorable condition for viral replication.

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SIRT6 Depletion Suppresses Tumor Growth by Promoting Cellular Senescence Induced by DNA Damage in HCC

Cited by 36 publications

References 42 publications

Suppression of SIRT6 by miR-33a facilitates tumor growth of glioma through apoptosis and oxidative stress resistance

Suppression of SIRT6 by miR-33a facilitates tumor growth of glioma through apoptosis and oxidative stress resistance

Overexpression of SIRT6 attenuates the tumorigenicity of hepatocellular carcinoma cells

RGNNV-induced cell cycle arrest at G1/S phase enhanced viral replication via p53-dependent pathway in GS cells

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