Function of the SIRT1 protein deacetylase in cancer

Stünkel, Walter; Peh, Bee Keow; Tan, Yong; Nayagam, Vasantha M.; Wang, Xukun; Salto-Tellez, Manuel; Ni, Binhui; Entzeroth, Michael; Wood, Jeanette M.

doi:10.1002/biot.200700087

Cited by 210 publications

(189 citation statements)

References 40 publications

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“…To examine whether SIRT1 expression is altered in human cancers, we have tested the expression levels of SIRT1 in breast and ovarian cancers. Consistent with the earlier studies that SIRT1 is overexpressed in cancer cell lines and various cancers (Huffman et al, 2007;Stu¨nkel et al, 2007), we found that the levels of SIRT1 are elevated in both ovarian and breast cancers ( Figure 6 and data not shown). Interestingly, SIRT1 levels inversely correlate with the levels of acetylated cortactin in breast tissue specimens, further suggesting that SIRT1 is one of the deacetylases for cortactin in vivo.…”

Section: Discussionsupporting

confidence: 93%

“…SIRT1, although mainly localized in the nucleus, can be shuttled to the cytoplasm (Tanno et al, 2007). A recent study showed that human SIRT1 is highly expressed in the cytoplasm in tissue samples from colon carcinoma patients (Stu¨nkel et al, 2007). SIRT1 was present in the cytoplasm in pancreatic islet a and b cells (Moynihan et al, 2005) and was also found to be cytosolic in C2C12 myoblast cells after differentiation (Tanno et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

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Deacetylation of cortactin by SIRT1 promotes cell migration

et al. 2008

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Cortactin binds F-actin and promotes cell migration. We showed earlier that cortactin is acetylated. Here, we identify SIRT1 (a class III histone deacetylase) as a cortactin deacetylase and p300 as a cortactin acetylase. We show that SIRT1 deacetylates cortactin in vivo and in vitro and that the SIRT1 inhibitor EX-527 increases amounts of acetylated cortactin in ovarian cancer cells. We also show that p300 acetylates cortactin in vivo and that cells lacking or depleted of p300 express lessacetylated cortactin than do control cells. Deletion analysis mapped the SIRT1-binding domain of cortactin to its repeat region, which also binds F-actin. Mouse embryo fibroblasts (MEFs) lacking sir2a (the mouse homolog of SIRT1) migrated more slowly than did wildtype cells. The expression of SIRT1 in sir2a-null cells restored migratory capacity, as did expression of a deacetylation-mimetic mutant of cortactin. SIRT1 and cortactin were more abundant in breast tumor tissue than in their normal counterparts, whereas SIRT1 expression inversely correlates with the ratio of acetylation cortactin versus total cortactin. These data suggest that deacetylation of cortactin is associated with high levels of SIRT1 and tumorigenesis. Finally, breast and ovarian cancer cell lines expressing an acetylation mimetic mutant of cortactin are less motile than that of control cells, whereas cells expressing the deacetylation mimetic mutant of cortactin migrate faster than that of control cells in Transwell migration assays. In summary, our results suggest that cortactin is a novel substrate for SIRT1 and p300 and, for the first time, a possible role for SIRT1 in cell motility through deacetylation of cortactin.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Deacetylation of cortactin by SIRT1 promotes cell migration

et al. 2008

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“…malignancies (6,42), and changes in SIRT1-mediated signaling allows mammalian cells to survive under oxidative stress and DNA damage, which are closely associated with tumorigenesis (43,44), cancer progression and poor prognosis in cancer patients (3,4,36). The present study identified an association of SIRT1 overexpression with shorter OS time and poor prognostic indicators in SCC, which was consistent with the results of previous studies (4,36,45).…”

Section: A B C Dsupporting

confidence: 92%

Association of SIRT1 and HMGA1 expression in non-small cell lung cancer

Lin¹,

Peng²

2015

Oncology Letters

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Abstract. The roles of Silent mating type information regulation 2 homolog 1 (SIRT1) and High mobility group A1 (HMGA1) in human diseases have been extensively studied separately; however, to the best of our knowledge, the current study is the first to report on their interrelationship in lung cancer. The association of SIRT1 and HMGA1 in non-small cell lung cancer (NSCLC) was investigated by evaluating their expression and prognostic significance in 260 patients with NSCLC using immunohistochemistry. SIRT1 and HMGA1 expression were found to be significantly correlated with each other (P<0.001), and both were significantly associated with clinicopathological parameters, including histological type and degree of differentiation. In squamous cell carcinoma (SCC), SIRT1 + specimens were significantly associated with shorter overall survival (OS) time (P=0.019). However, in patients with adenocarcinoma (AD), no association was identified between SIRT1 and OS. In addition, HMGA1 + specimens were significantly associated with poor differentiation (P=0.028), and were more frequent in SCC than AD (P=0.015). However, HMGA1 was not associated with OS on univariate Cox regression analysis or Kaplan-Meier analysis (both P>0.05). SIRT1/HMGA1 coexpression was significantly associated with male gender (P=0.016), and moderately and poorly differentiated histological grade (P=0.025). The findings indicate that SIRT1 and HMGA1 may have significant effects during tumor progression in NSCLC, particularly in patients with SCC, and are potentially useful as prognostic indicators for patients with NSCLC.

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“…SIRT1 expression is significantly elevated in prostate and colon cancers (Huffman et al, 2007;Stunkel et al, 2007), and HIC1 (hypermethylated in cancer 1), an inhibitor of SIRT1 transcription, is epigenetically silenced in many tumors (Chen et al, 2005). SIRT1 has however in addition to H4K16 been shown to be a protein deacetylase, and plural effects of SIRT1 on cell survival have been reported.…”

Section: Discussionmentioning

confidence: 99%

Opposing effects of hMOF and SIRT1 on H4K16 acetylation and the sensitivity to the topoisomerase II inhibitor etoposide

Wallenborg

Vlachos

et al. 2010

Oncogene

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Various inhibitors of histone deacetylase (HDAC) activity can sensitize drug resistant cancer cells to chemotherapeutic agents. However, the mechanisms underlying such effects of distinct HDAC inhibitors (HDACi) remain poorly understood. Here we show that both the HDACi trichostatin A and valproic acid induced a sensitization of multidrug-resistant cancer cells to the topoisomerase II inhibitor etoposide/VP16. This effect was associated with increased acetylation of certain lysines on histones H3 and H4, including lysine 16 on histone H4 (H4K16). Overexpression of the histone acetyltransferase hMOF, known to target H4K16, was sufficient to mimic HDACi treatment on sensitization and H4K16 acetylation, and importantly, small-interfering RNA (siRNA)-mediated knockdown of hMOF abolished the HDACi-mediated sensitizing effects as well as the increase in H4K16 acetylation. Conversely, siRNA-mediated knockdown of the H4K16 deacetylase SIRT1 mimicked HDACi treatment whereas overexpression of SIRT1 abolished H4K16 acetylation and significantly reduced the sensitizing effects of HDACi. Interestingly, the effects of hMOF on H4K16 acetylation and sensitization to the topoisomerase II inhibitor could be directly counteracted by exogenous expression of increasing amounts of SIRT1 and vice versa. Our study results suggest that hMOF and SIRT1 activities are critical parameters in HDACi-mediated sensitization of multidrug-resistant cancer cells to topoisomerase II inhibitor and increased H4K16 acetylation.

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Function of the SIRT1 protein deacetylase in cancer

Cited by 210 publications

References 40 publications

Deacetylation of cortactin by SIRT1 promotes cell migration

Deacetylation of cortactin by SIRT1 promotes cell migration

Association of SIRT1 and HMGA1 expression in non-small cell lung cancer

Opposing effects of hMOF and SIRT1 on H4K16 acetylation and the sensitivity to the topoisomerase II inhibitor etoposide

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