The novel prognostic marker, EHMT2, is involved in cell proliferation via HSPD1 regulation in breast cancer

Kim, Seon‐Kyu; Kim, Kwang‐Ho; Ryu, Jeong-Min; Ryu, T; Lim, Jung Hwa; Oh, Jung‐Hwa; Kim, Jung Min; Jung, Cho‐Rok; Hamamoto, Ryuji; Son, Mi‐Young; Kim, Dae‐Soo; Cho, Hyun Soo

doi:10.3892/ijo.2018.4608

Cited by 23 publications

(24 citation statements)

References 27 publications

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“…The human breast cancer cell line MDA-MB-231 was purchased from the Korean Cell Line Bank (Seoul, South Korea) and cultured at 37 o C in DMEM supplemented with 10% fetal bovine serum (FBS) and 1% penicillin/streptomycin in a humidified atmosphere with 5% CO2 (30).…”

Section: Cell Culturementioning

confidence: 99%

SETDB1 regulates SMAD7 expression for breast cancer metastasis

Ryu

Kim

et al. 2019

BMB Rep.

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Breast cancer (BRC) is the most invasive cancer in women. Although the survival rate of BRC is gradually increasing due to improved screening systems, development of novel therapeutic targets for inhibition of BRC proliferation, metastasis and recurrence have been constantly needed. Thus, in this study, we identified overexpression of SETDB1 (SET Domain Bifurcated 1), a histone methyltransferase, in RNA-seq data of BRC derived from TCGA portal. In Gene Ontology (GO) analysis, cell migration-related GO terms were enriched, and we confirmed down-regulation of cell migration/invasion and alteration of EMT /MET markers after knockdown of SETDB1. Moreover, gene network analysis showed that SMAD7 expression is regulated by SETDB1 levels, indicating that up-regulation of SMAD7 by SETDB1 knockdown inhibited BRC metastasis. Therefore, development of SETDB1 inhibitors and functional studies may help develop more effective clinical guidelines for BRC treatment. [BMB Reports 2019; 52(2): 139-144]

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Section: Cell Culturementioning

confidence: 99%

SETDB1 regulates SMAD7 expression for breast cancer metastasis

Ryu

Kim

et al. 2019

BMB Rep.

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“…EHMT2 is an HMT that is involved in H3K9 dimethylation for the formation of heterochromatin in transcriptional gene regulation. Moreover, in breast, bladder and lung cancer, knockdown of EHMT2 was shown to be involved in cell apoptosis and cell migration/invasion [26][27][28]30]. After treatment with SP in the CRC cell lines, we could not detect any changes in EHMT2 at the transcriptional level, but in western blot analysis, the expression of EHMT2 was significantly reduced ( Fig.…”

Section: Ehmt2 Is a Target For Propionate-induced Cell Apoptosis In Cmentioning

confidence: 88%

“…Among them, euchromatic histone-lysine N-methyltransferase 2 (EHMT2) carried out mono-and dimethylation of histone H3 lysine 9 to generate heterochromatin for the repression of tumor suppressor genes. Knockdown of EHMT2 by siRNA resulted in cell apoptosis, cell cycle arrest, and metastasis in several types of cancer [26][27][28]. Although EHMT2 is an important therapeutic target for CRC treatment, the regulation of EHMT2 expression in CRC, especially the relationship between EHMT2 and the human microbiome, remains elusive.…”

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confidence: 99%

Histone methyltransferase EHMT2 degradation by propionate derived from Bacteroides thetaiotaomicron induced colon cancer apoptosis via epigenetic regulation of TNFAIP1

Ryu¹,

Kim²,

Han³

et al. 2020

Preprint

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BackgroundBacteroides thetaiotaomicron (BT) is the second most commonly isolated bacterium in the human microbiome after B. fragilis and is involved in the hydrolysis of glycosidic bonds in dietary carbohydrates. Although the human microbiome has recently been shown to affect colorectal cancer (CRC) treatment, the mode of action (MOA) between the microbiome and CRC is still unclear. MethodsTo assess the colon cancer apoptosis, we performed western blot, qRT-PCR and FACS analysis using BT supernatant (Sup), sodium propionate (SP), and EHMT2 specific siRNA. Using RNA-seq analysis and ChIP-seq analysis, we identified HECTD2 (E3 ligase) and TNFAIP1 (EHMT2 target) genes. The antitumor activity of EHMT2 was determined by an in vivo xenograft model. ResultsWe selected propionate derived from BT and showed that it suppressed CRC growth by promoting proteasomal degradation of EHMT2 through HECTD2 upregulation. Moreover, downregulation of EHMT2 reduced the level of H3K9me2 on the promoter region of TNFAIP1, and subsequently, upregulation of TNFAIP1 induced apoptosis of CRC cells. Finally, we performed an in vivo study using BIX01294 to inactivate EHMT2 and observed a reduction in the tumor size of the CRC xenograft models. ConclusionsWe suggest anticancer effects of BT and EHMT2 as therapeutic targets for colon cancer treatment, and we will provide the possibility for synergistic effects of an EHMT2 inhibitor and BT in CRC treatment. *Authors share co-first authorshipBackground Colorectal cancer (CRC) is a major cancer worldwide. Although chemotherapy (5-fluorouracil (5-FU) and oxaliplatin) and targeted therapy (cetuximab and bevacizumab) are used to treat this disease, new therapeutic methods are needed to reduce the side effects and increase the success rate of CRC 4 treatment [1][2][3]. Recently, the human microbiome, including metabolites and microbiota, has been studied to identify alternative new CRC treatments [4][5][6].In the human body, the microbiota mainly colonizes the large intestine and promotes food digestion, regulation of the human immune system, production of vitamins (B12, K, riboflavin), and protection against disease-related bacteria [7][8][9]. In the colon, the Bacteroides genus is a major group of the human microbiome, and Bacteroides thetaiotaomicron (BT) is the second most commonly isolated bacteria after B. fragilis [10][11][12]. BT is a gram-negative obligate anaerobe. This bacterium is involved in polysaccharide metabolism, such as hydrolysis of glycosidic bonds in dietary carbohydrates [10]. In colon cancer, the major bacterium B. fragilis showed suppression of inflammation-associated CRC development via polysaccharide A production [13]. In other words, B. fragilis-derived toxins induced CRC development [14]. Although BT is the second most commonly isolated bacterium in the human microbiome, the relationship between BT and CRC is still unclear. Thus, we examined the anticancer effects of BT using CRC cell lines and elucidated the molecular mechanism of BT-induced apoptosis of CRC cells via epig...

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“…The role of HSP60 in apoptosis is quite conflicting. To support its anti-apoptotic function, knockdown of HSP60 has been found to promote apoptosis in cardiac myocytes, hepatocellular carcinoma (HCC), and breast cancer cells [11,12,32]. In an inducible cardiac-specific HSP60 knockout mouse model, it has been demonstrated that HSP60 deletion in adult hearts leads to an increased number of apoptotic cardiac myocytes, accompanied by altering mitochondrial complex activity, mitochondrial membrane potential (∆Ψm), and reactive oxidative species production.…”

Section: Hsp60 Functions In Normal and Cancer Cellsmentioning

confidence: 99%

Functional Compartmentalization of HSP60-Survivin Interaction between Mitochondria and Cytosol in Cancer Cells

Huang

Yeh

2019

Cells

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Heat shock protein 60 (HSP60) and survivin reside in both the cytosolic and mitochondrial compartments under physiological conditions. They can form HSP60-survivin complexes through protein-protein interactions. Their expression levels in cancer tissues are positively correlated and higher expression of either protein is associated with poor clinical prognosis. The subcellular location of HSP60-survivin complex in either the cytosol or mitochondria is cell type-dependent, while the biological significance of HSP60-survivin interaction remains elusive. Current knowledge indicates that the function of HSP60 partly rests on where HSP60-survivin interaction takes place. HSP60 has a pro-survival function when binding to survivin in the mitochondria through interacting with other factors such as CCAR2 and p53. In response to cell death signals, mitochondrial survivin functions through preventing procaspase activation. Degradation of cytosolic survivin leads to the loss of mitochondrial membrane potential and aberrant mitosis processes. On the other hand, HSP60 release from mitochondria to cytosol upon death stimuli might exert a pro-death function, either through stabilizing Bax, enhancing procaspase-3 activation, or increasing protein ubiquitination. Combining the knowledge of mitochondrial HSP60-survivin complex function, cytosolic survivin degradation effect, and pro-death function upon mitochondria release of HSP60, a hypothetical scenario for HSP60-survivin shuttling upon death stimuli is proposed.

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The novel prognostic marker, EHMT2, is involved in cell proliferation via HSPD1 regulation in breast cancer

Cited by 23 publications

References 27 publications

SETDB1 regulates SMAD7 expression for breast cancer metastasis

SETDB1 regulates SMAD7 expression for breast cancer metastasis

Histone methyltransferase EHMT2 degradation by propionate derived from Bacteroides thetaiotaomicron induced colon cancer apoptosis via epigenetic regulation of TNFAIP1

Functional Compartmentalization of HSP60-Survivin Interaction between Mitochondria and Cytosol in Cancer Cells

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