Role of Klotho Protein in Tumor Genesis, Cancer Progression, and Prognosis in Patients with High-Grade Glioma

Peshes-Yeloz, Naama; Ungar, Lior; Wohl, Anton; Jacoby, Elad; Fisher, Tamar; Leitner, Moshe; Nass, Dvora; Rubinek, Tamar; Wolf, Ido

doi:10.1016/j.wneu.2019.06.082

Cited by 18 publications

(9 citation statements)

References 34 publications

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“…Tumor suppressor capabilities of KL have been implicated in numerous cancer types [ 12 , 13 , 16 , 24 , 30 , 31 ]. We and other research groups have found that KL is an anti-aging gene but has a lack of expression in lung cancer, and that it plays an important role in the development of lung cancer, drug resistance, etc.…”

Section: Discussionmentioning

confidence: 99%

“…Klotho (KL) is a potent tumor suppressor in many malignancies, including colorectal, glioma, melanoma, and ovarian cancers [ 12 – 16 ]. Several signal mechanisms have been reported to be involved in the tumor suppressor activity of KL, including the IGF-1, FGF, and Wnt/β-catenin pathways [ 13 ], while the detailed working mode of KL in cancer is still a matter of controversy [ 17 – 19 ].…”

Section: Introductionmentioning

confidence: 99%

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SHANK1 facilitates non-small cell lung cancer processes through modulating the ubiquitination of Klotho by interacting with MDM2

Chen

Zhao

et al. 2022

Cell Death Dis

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SH3 and multiple ankyrin repeat domains 1 (SHANK1) is a scaffold protein, plays an important role in the normal function of neuron system. It has recently been shown to be a potential oncogene. In the present study, we report that the expression of SHANK1 is upregulated in non-small cell lung cancer (NSCLC), and is correlated with clinic pathological characteristics of NSCLC. Moreover, SHANK1 overexpression enhances the proliferation, migration and invasion of NSCLC cells. Mouse cell-derived xenograft model also confirmed the effects of SHANK1 on tumor growth in vivo. Furthermore, we found that SHANK1 increases the protein degradation of Klotho (KL), an important tumor suppressor, through ubiquitination-dependent pathway. In particular, we report discovery of KL as a SHANK1-interacting protein that acts as a new substate of the E3 ubiquitin ligase MDM2. SHANK1 can form a complex with KL and MDM2 and enhance the interaction between KL and MDM2. Our findings reveal an important oncogenic role and mechanism of SHANK1, suggesting SHANK1 can be a potential therapeutic target in NSCLC.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

SHANK1 facilitates non-small cell lung cancer processes through modulating the ubiquitination of Klotho by interacting with MDM2

Chen

Zhao

et al. 2022

Cell Death Dis

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“…Another upregulated DEG, Klotho-a newly discovered antiaging gene-encodes a transmembrane protein with an extracellular domain 34 . Klotho is mainly expressed in the brain and kidney 35,36 .…”

Section: Upregulated Degs In Shrs With Mamentioning

confidence: 99%

Exploring the Mechanisms of Acupuncture-Induced Lowering of Blood Pressure Through Positron Emission Tomography and RNA Sequencing of the PVH

Peng

Lai

et al. 2020

Preprint

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Manual acupuncture (MA) can be used to manage high blood pressure, however, the underlying molecular mechanism remains unknown. To explore the mechanism of acupuncture in the treatment of hypertension, we used Wistar Kyoto rats (WKYs) and spontaneously hypertensive rats (SHRs) that were subject to either MA stimulation or the corresponding sham procedure as a negative control (sham-MA) for 1 week. Blood pressure was recorded regularly. After 7 days of treatment, PET-CT scans were used to detect brain areas where glucose metabolism was significantly regulated. Additionally, the differentially expressed genes(DEGs) of a specific brain region—the paraventricular hypothalamic nucleus (PVH)—were evaluated by transcriptomics, and verified with quantitative PCR (qPCR). Eight overlapping DEGs were found between the WKY, SHR, and MA groups. The DEGs were then annotated with the Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) databases. qPCR was used to verify the DEGs. These genes may lower blood pressure by regulating angiotensin, endothelial function and inflammation, ect. This study reveals MA regulates multiple biological processes and genes of the PVH, and provides a solid theoretical basis for exploring the mechanisms by which MA manages hypertension.

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“…Meanwhile, alpha‐Klotho is cleaved by secretases ADAM 10 and 17, 12 and secreted from cells into the blood, cerebrospinal fluid and urine, 13–15 as has not been reported for β‐Klotho or γ‐Klotho so far. Recent research indicated that α‐Klotho, designated as Klotho, was involved in the progression of a variety of human cancers as a tumor suppressor, including hepatocellular carcinoma, colorectal cancer, renal cell carcinoma, pancreatic cancer, breast cancer, and lung cancer and so on 16 . However, these conclusions are limited to experimental studies and a few clinical studies, mainly evaluating the tissue Klotho expression level.…”

Section: Introductionmentioning

confidence: 99%

Association of serum Klotho levels with cancer and cancer mortality: Evidence from National Health and Nutrition Examination Survey

Qiao

Liu

et al. 2022

Cancer Medicine

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Background Klotho has both anticancer and hormone‐like functions. But the research on Klotho and cancer is mainly based on animal experiments and small‐scale clinical research, thus we explored the association between serum Klotho and cancer and cancer mortality based on the National Health and Nutrition Survey (NHANES). Methods Participants were employed from the NHANES 2007–2016, excluding pregnant, chronic renal insufficiency, and incomplete data of cancer questionnaire and serum Klotho level. The association of serum Klotho with cancer and mortality was analyzed by weighted Logistic regression, weighted Cox regression and competitive risk model, respectively. Correlations between serum Klotho and testosterone and estradiol levels were analyzed by Spearman correlation and restricted cubic spline respectively. Results We found Klotho had an inverse effect with risk of pan‐cancer (all p < 0.02), with each unit increase in Klotho (1ug/g creatinine) associated with a 0.9%–2.2% reduction in the risk of cancer, and higher levels showing a stronger negative association (all p‐trend <= 0.0005). Whereas, we did not observe any association between serum Klotho level with all‐cause mortality and cancer‐specific mortality (all p > 0.05). Then, stratified analysis found that people aged 60–79, female, overweight and non‐Hispanic whites or Mexican Americans were less likely to develop cancer. In addition, there was a strong nonlinear and linear positive correlation of Klotho with estradiol (p‐nonlinear = 0.0178) and testosterone only among male participants (β = −0.513, p = 0.0137), respectively. Conclusions We found an inverse association between serum Klotho and cancer, but without cancer mortality. And this effect may be partially mediated by estradiol and testosterone. Further prospective studies are needed to prove these findings.

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Role of Klotho Protein in Tumor Genesis, Cancer Progression, and Prognosis in Patients with High-Grade Glioma

Cited by 18 publications

References 34 publications

SHANK1 facilitates non-small cell lung cancer processes through modulating the ubiquitination of Klotho by interacting with MDM2

SHANK1 facilitates non-small cell lung cancer processes through modulating the ubiquitination of Klotho by interacting with MDM2

Exploring the Mechanisms of Acupuncture-Induced Lowering of Blood Pressure Through Positron Emission Tomography and RNA Sequencing of the PVH

Association of serum Klotho levels with cancer and cancer mortality: Evidence from National Health and Nutrition Examination Survey

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