Histone methyltransferase KMT5A gene modulates oncogenesis and lipid metabolism of papillary thyroid cancer inï¿½vitro

Liao, Tian; Wang, Yuan Jin; Hu, Jia; Wang, Yu; Han, Li; Ma, Ben; Shi, Rong; Qu, Ning; Wei, Wen Jun; Guan, Qing; Xiang, Jun; Chen, Jia Ying; Sun, Guo Hua; Li, Duan Shu; Mu, Xiang Ming; Ji, Qing

doi:10.3892/or.2018.6295

Cited by 37 publications

(41 citation statements)

References 27 publications

(27 reference statements)

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“…Preliminary exploration of lipid metabolism in patients with TC revealed the existence of lipid metabolism disorders (27). The present study demonstrated that ApoA1 and HDL-C levels, which have positive effects in human metabolism, were decreased Conversely, TG level and LDL-C/HDL-C ratio, which Table IV.…”

Section: Discussionsupporting

confidence: 52%

Comparative analysis of the serum proteome profiles of thyroid cancer: An initial focus on the lipid profile

Zhou

et al. 2019

Oncol Lett

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The serum lipid profile and clinical outcomes of cancer patients are commonly correlated in a wide range of carcinomas. However, few studies have investigated the serum lipid profile of patients with thyroid cancer (TC). The present study therefore aimed to analyze the lipid profiles of patients with TC. The serum proteomes of 31 participants with stage I-IV TC were screened using Orbitrap Q Exactive Plus. Analytical data collected between November 1, 2013 and November 11, 2018 from the laboratory information system included the total cholesterol (CHO), triglyceride (TG), high-density lipoprotein-cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein A1 (ApoA1), lipoprotein (a) and apolipoprotein B (ApoB) levels that were used to validate the screening results. A total of 3875 outpatients were enrolled in this study. A number of 17 differentially expressed proteins were identified. An Ingenuity pathway analysis identified activation of the liver X receptor/retinoid X receptor (LXR/RXR) activation, which is a crucial pathway involved in lipid metabolism. The results demonstrated that the total CHO levels were significantly different between patients with TC and control groups, both in men and women. In women, the levels of TG, HDL-C, Apo A1 and LDL-C/HDL-C were significantly different between patients with TC and control groups (all P<0.05). Higher concentrations of TG and LDL-C/HDL-C were observed in the cancer group compared with the control group. However, lower levels of Apo A1 and HDL-C were observed in women from the cancer group compared with the control group. The results from the present study revealed the presence of a disordered lipid profile in patients with TC. The molecular mechanism underlying the association between lipid metabolism and cancer requires further investigation and may be used to develop novel diagnostic biomarkers and therapeutic targets in human cancers.

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Section: Discussionsupporting

confidence: 52%

Comparative analysis of the serum proteome profiles of thyroid cancer: An initial focus on the lipid profile

Zhou

et al. 2019

Oncol Lett

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“…Consistent with this, the overexpression of SETD8 has been reported in many different solid tumors [14][15][16][17] and pharmacological inhibition of SETD8 is sufficient to activate the p53 pro-apoptotic program in neuroblastoma cell lines 18 . This has suggested that this enzyme could be an attractive target to rescue p53 functions in cancers displaying a low incidence of p53 genetic alterations, as it is the case at early stages in multiple myeloma 19 .…”

Section: Introductionsupporting

confidence: 70%

“…An up-regulation of SETD8 is not specific to multiple myeloma, as it has also been observed in different types of solid tumors 11 , such as papillary thyroid cancer 16 , breast carcinoma 14,26 , and childhood tumors of the nervous system 15,18 . However, the mechanisms that contribute to elevated levels of SETD8 in cancer still remained unclear.…”

Section: Pharmacological Inhibition Of Setd8 Synergizes With Melphalamentioning

confidence: 99%

Targeting the methyltransferase SETD8 impairs tumor cell survival and overcomes drug resistance independently of p53 status in multiple myeloma

Herviou

Izard

Karmous-Gadacha³

et al. 2019

Preprint

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Multiple myeloma (MM) is a malignancy of plasma cells that largely remains incurable.The search for new therapeutic targets is therefore essential. Here we show that a higher expression of the lysine methyltransferase SETD8, which is responsible for histone H4K20 mono-methylation, is an adverse prognosis factor associated with a poor outcome in two cohorts of newly diagnosed patients. Remarkably, primary malignant plasma cells are particularly addicted to SETD8 activity. Indeed, pharmacological inhibition of this enzyme by the chemical compound UNC0379 demonstrated a significantly higher toxicity in MM cells compared to normal cells from the bone marrow microenvironment. Moreover, RNA sequencing and functional studies revealed that SETD8 inhibition induces a mature non-proliferating plasma cell signature and an activation of the p53 canonical pathway, which together leads to an impairment of myeloma cell proliferation and survival. However, UNC0379 treatment triggers a deadly level of replicative stress in p53 deficient MM cells, indicating that the cytotoxicity associated with SETD8 inhibition is independent of the p53 status. Consistent with this, the combination of UNC0379 with the conventional cytotoxic agent melphalan strongly enhances DNA damage and overcomes drug resistance in myeloma cells.Thus, targeting SETD8 could be of therapeutic interest to improve MM treatment in highrisk patients independently of the p53 status.3

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“…SET8 is functional in multiple cellular pathways, such as DNA replication, chromosome compaction, cell cycle progression, transcriptional modulation, genomic instability, and cellular metabolism [17][18][19][20]. Moreover, SET8 is involved in cancer proliferation, invasiveness, and migration and is thus associated with a poor survival rate in cancer patients [21,22]. Some reports show that high methyltransferase activity of SET8 is associated with a high recurrence rate and poor overall survival rate in patients with liver cancer [23].…”

Section: Introductionmentioning

confidence: 99%

Fasting Induces Hepatocellular Carcinoma Cell Apoptosis by Inhibiting SET8 Expression

Chen

et al. 2020

Oxidative Medicine and Cellular Longevity

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Background. Hepatocellular carcinoma (HCC) is a life-threatening cancer, and the Kelch-like ECH-associated protein 1 (Keap1)/NF-E2-related factor 2 (Nrf2)/antioxidant response element (ARE) signalling pathway plays a crucial role in apoptosis resistance in cancer cells. Fasting is reported to mediate tumour growth reduction and apoptosis. SET8 is involved in cancer proliferation, invasiveness, and migration. However, whether SET8 participates in fasting-mediated apoptosis in HCC remains unclear. Methods. We used immunohistochemical staining to analyse the expression of SET8, Keap1, and Nrf2 in HCC tissues. Cell viability, apoptosis, and cellular reactive oxygen species (ROS) were assessed, and Western blot and qPCR analyses were used to examine the expression of Keap1/Nrf2 in HCC cells under fasting, SET8 overexpression, and PGC1α overexpression conditions. Mass spectrometry, coimmunoprecipitation, and confocal microscopy were used to determine whether PGC1α interacts with SET8. In vivo experiments were performed to verify the conclusions from the in vitro experiments. Results. Our data indicate that SET8 expression is associated with poor survival in HCC patients. Both in vitro and in vivo results demonstrated that fasting decreased cell viability and downregulated expression of SET8, Nrf2, and downstream effectors of Nrf2, while it upregulated Keap1 expression, mediated ROS accumulation, and induced HCC cell apoptosis. These results were similar to what is observed in SET8-deficient cells. Furthermore, SET8 was found to interact with PGC1α, and both PGC1α and H4K20me1, a downstream target of SET8, were found to be enriched at the Keap1 promoter region. These two factors were further determined to attenuate Keap1 promoter activity. Conclusions. The results of our study demonstrate that fasting induces HCC apoptosis by inhibiting SET8 expression and that SET8 interacts with PGC1α to activate the Nrf2/ARE signalling pathway by inhibiting Keap1 expression.

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Histone methyltransferase KMT5A gene modulates oncogenesis and lipid metabolism of papillary thyroid cancer inï¿½vitro

Cited by 37 publications

References 27 publications

Comparative analysis of the serum proteome profiles of thyroid cancer: An initial focus on the lipid profile

Comparative analysis of the serum proteome profiles of thyroid cancer: An initial focus on the lipid profile

Targeting the methyltransferase SETD8 impairs tumor cell survival and overcomes drug resistance independently of p53 status in multiple myeloma

Fasting Induces Hepatocellular Carcinoma Cell Apoptosis by Inhibiting SET8 Expression

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