Klotho Acts as a Tumor Suppressor in Cancers

Xie, Biao; Chen, Jinhui; Liu, Bin; Zhan, Jicheng

doi:10.1007/s12253-013-9663-8

Cited by 61 publications

(58 citation statements)

References 75 publications

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“…KLOTHO , a novel cell-cycle regulatory TSG, has been reported to be transcriptionally silenced in MDA-MB-231 cells (Wolf et al, 2008; Xie et al, 2013). Treatment with the combinations of 20 μg/mL GTPs and 10 μM SFN significantly ( P < 0.001) reactivated mRNA expression of KLOTHO by 11.2-, 11.4- and 20.2-fold in MDA-MB-231 cells at 24, 48 and 72 h, respectively, as compared to their respective controls (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Expression of p21 CIP1/WAF1 has been shown to be epigenetically silenced in many cancers including breast cancer (Chen et al, 2013a; Chew et al, 2012). In addition to p21 CIP1/WAF1 , KLOTHO, a novel 1012-amino acid transmembrane protein, has also been shown to play major role as a tumor suppressor, mainly by inhibiting IGF-1/insulin pathways in many cancer subtypes (Doi et al, 2011; Lee et al, 2010; Wolf et al, 2008; Xie et al, 2013). In addition, upregulation of KLOTHO has been positively correlated with the suppression of cancer metastasis through inhibition of transforming growth factor-β1 signaling (Doi et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

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Epigenetic reactivation of p21CIP1/WAF1 and KLOTHO by a combination of bioactive dietary supplements is partially ERα-dependent in ERα-negative human breast cancer cells

Sinha

Shukla

Khan

et al. 2015

Molecular and Cellular Endocrinology

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Available treatment strategies against estrogen receptor (ER)-negative breast cancer patients are limited due to their poor response to hormonal therapy. We have shown previously that the combinations of green tea polyphenols (GTPs), a dietary DNA methyltransferase inhibitor, and sulforaphane (SFN), a dietary histone deacetylase inhibitor, reactivate ERα expression in ERα-negative MDA-MB-231 cells. Here, we investigated the functional significance of ERα reactivation in the reactivation of silenced tumor suppressor genes (TSGs) in ERα-negative human breast cancer cells. We found that the treatment of MDA-MB-231 cells with the combinations of GTPs and SFN leads to the reactivation of silenced TSGs such as p21CIP1/WAF1 and KLOTHO through active chromatin modifications. Further, GTPs- and SFN-mediated reactivation of TSGs was, at least in part, dependent on ERα reactivation in ERα-negative MDA-MB-231 cells. Collectively, our findings suggest that a novel combination of bioactive dietary supplements could further be explored as an effective therapeutic option against hormonal refractory breast cancer.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Epigenetic reactivation of p21CIP1/WAF1 and KLOTHO by a combination of bioactive dietary supplements is partially ERα-dependent in ERα-negative human breast cancer cells

Sinha

Shukla

Khan

et al. 2015

Molecular and Cellular Endocrinology

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“…Since that publication, the role of klotho in tumorigenesis, cancer progression, and prognosis has attracted increasing attention. 23 Recent studies have shown that klotho participates in the progression of several types of human cancer, including lung cancer, gastric cancer and pancreatic adenocarcinoma. 23 In the majority of these malignant tumors, klotho acts as a tumor suppressor gene.…”

Section: Discussionmentioning

confidence: 99%

Klotho: a tumor suppressor and modulator of the Wnt/β-catenin pathway in human hepatocellular carcinoma

Tang

Wang

Fan

et al. 2016

Laboratory Investigation

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Klotho, an anti-aging gene, has recently been shown to contribute to human hepatic tumorigenesis. In addition, it is known that Wnt signaling is antagonized by the protein klotho. Because augmented Wnt signaling has an important role in tumorigenesis of human hepatocellular carcinoma (HCC), we studied the relationship of klotho expression and activity to the Wnt pathway in this malignancy. Immunohistochemical analysis performed on tissue arrays revealed that klotho expression levels were significantly lower in HCC than in adjacent noncancerous tissues, while klotho staining was inversely correlated with clinical stage and histologic grade. Patients with klotho-expressing tumors had longer survival periods than did those with klotho-negative tumors. Overexpression of klotho as well as treatment with soluble klotho protein reduced hepatoma cell growth in vitro and in vivo, whereas klotho silencing enhanced cellular proliferation. Moreover, forced expression of klotho inhibited Wnt/β-catenin signaling, as confirmed by reduced expression of β-catenin, inhibition of translocation of β-catenin from the cytoplasm to the nucleus, and reduced expression of c-myc and cyclin D1, two known target genes of the Wnt/β-catenin pathway. In contrast, activation of the Wnt/β-catenin pathway was enhanced when klotho was silenced by inhibitory RNAs. Furthermore, serum levels of soluble klotho in patients with malignant tumors were studied, and results suggested a significant increase in these levels in HCC patients. These data suggest that klotho acts as a tumor suppressor and an inhibitor of the Wnt/β-catenin pathway in HCC, and moreover, that soluble klotho is a potential serum biomarker for HCC.

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“…The physiological and pathological function of KL shows it can be used as a regulator of oxidative stress and senescence (3). Moreover, recent studies show that KL is involved in the progression of several types of human cancers, and plays an important role in tumorigenesis, proliferation, survival, autophagy and resistance to antitumor therapies (4). KL is inactivated through promoter hypermethylation and potentially functions as a tumor suppressor gene in human cancers (5,6), suggesting loss of KL may serve as an early marker for breast tumorigenesis (7).…”

Section: Introductionmentioning

confidence: 99%

Klotho suppresses growth and invasion of colon cancer cells through inhibition of IGF1R-mediated PI3K/AKT pathway

Huang

Peng

et al. 2014

International Journal of Oncology

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Klotho (KL) was originally characterized as an aging suppressor gene, and has been identified as a tumor suppressor gene in a variety of cancers including colon cancer. However, the potential role and molecular events for KL in colon cancer remain unclear. The present study aimed to investigate the expression of KL in human colon cancer by immunohistochemistry, and to analyze the correlation between KL expression and clinicopathological characteristics of patients with colon cancer. Functional analysis after lentivirus-mediated gain of KL expression was used to assess the tumor growth and invasion in colon cancer cells in vitro and in vivo. The rate of KL expression was significantly decreased in cancer tissues compared with that in adjacent non-cancer tissues (ANCT) (60.3 vs.77.9%, P=0.022), and KL expression was negatively associated with Dukes staging (P=0.034) and depth of tumor invasion (P=0.008). Overexpression of KL in vitro inhibited cell proliferative activities and invasive potential in colon cancer cells, companied with decreased expression of p-IGF1R, p-PI3K, p-AKT, PCNA and MMP-2. In addition, the tumor volumes in the HT-29 subcutaneous tumor model treated with lentivirus‑mediated KL vector (Lv-KL) was significantly smaller than those of the negative control (NC) group (P<0.01). Taken together, our findings indicate that the expression of KL is downregulated in human colon caner and correlates with tumor invasion and Dukes staging, while overexpression of KL suppresses growth and invasion through inhibition of IGF1R-mediated PI3K/AKT pathway in colon cancer cells, suggesting that KL may serve as a potential therapeutic target for the treatment of colon cancer.

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Klotho Acts as a Tumor Suppressor in Cancers

Cited by 61 publications

References 75 publications

Epigenetic reactivation of p21CIP1/WAF1 and KLOTHO by a combination of bioactive dietary supplements is partially ERα-dependent in ERα-negative human breast cancer cells

Epigenetic reactivation of p21CIP1/WAF1 and KLOTHO by a combination of bioactive dietary supplements is partially ERα-dependent in ERα-negative human breast cancer cells

Klotho: a tumor suppressor and modulator of the Wnt/β-catenin pathway in human hepatocellular carcinoma

Klotho suppresses growth and invasion of colon cancer cells through inhibition of IGF1R-mediated PI3K/AKT pathway

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