EZH2 inhibition sensitizes tamoxifen‑resistant breast cancer cells through cell cycle regulation

Chen, Si; Yao, Fan; Xiao, Qinghuan; Liu, Qiannan; Yang, Yikun; Li, Xuejuan; Jiang, Guanglie; Kuno, Toshiki; Fang, Yue

doi:10.3892/mmr.2017.8160

Cited by 8 publications

(14 citation statements)

References 45 publications

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“…Moreover, EZH2 is involved in various physiological or pathological processes, most of which are achieved through the regulation of cell growth, proliferation, senescence, or apoptosis [ 29 – 32 ]. Consistently, prior research discovered that EZH2 knockdown resulted in repression of cell proliferation and cell cycle entry in breast cancer, accompanied by a decline in cyclin D1 expression [ 33 ]. Also, EZH2 inhibition resulted in the subsequent reduction in myeloma cell proliferation and an increase in cell cycle entry [ 34 ].…”

Section: Discussionsupporting

confidence: 59%

SMYD2 aggravates gastrointestinal stromal tumor via upregulation of EZH2 and downregulation of TET1

Long

et al. 2022

Cell Death Discov.

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SMYD2, as an oncogene, has been involved in multiple types of cancer, but the potential role of SMYD2 in gastrointestinal stromal tumors (GIST) remains enigmatic and requires further investigation. Hence, this study was conducted with the main objective of analyzing the effect of SMYD2 on GIST. GIST and adjacent normal tissues were collected from 46 patients with GIST where the expression of EZH2, SMYD2, and TET1 was determined, followed by the analysis of their interactions. The functional role of SMYD2 in cell biological functions was determined using a loss-of-function assay in GIST-T1 cells. Nude mouse xenograft experiments were performed to verify the role of the SMYD2/EZH2/TET1 axis in GIST in vivo. EZH2 was upregulated in GIST tissues and cell lines, which was positively correlated with SMYD2 expression and inversely correlated with TET1 expression in GIST tissues. EZH2 silencing due to SMYD2 inhibition reduced GIST-T1 cell proliferation and accelerated cell senescence. EZH2 repressed TET1 expression by promoting H3K27me3 methylation in the TET1 promoter region. TET1 inhibition reversed the effect of EZH2 silencing on the biological functions of GIST-T1 cells. In vivo data further revealed the promoting effect of SMYD2 on the progression of GIST by regulating the EZH2/TET1 axis. Overall, this study demonstrates that SMYD2 can increase EZH2 expression while suppressing TET1 expression, thus accelerating GIST, and creating new treatment opportunities for GIST.

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Section: Discussionsupporting

confidence: 59%

SMYD2 aggravates gastrointestinal stromal tumor via upregulation of EZH2 and downregulation of TET1

Long

et al. 2022

Cell Death Discov.

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“…Over the last decade, researchers put efforts to illuminate the complex network of ER transcriptional effects such as ER/ERK/MAPK pathway and stress-activated protein kinase/c-junNH2 terminal kinase pathway and suggested that alterations of the elements in these signaling pathway play an important role in resistance to tamoxifen in breast cancer treatment. 28 – 30 Moreover, with the development of molecular research, several critical importance targets of breast cancer cells have been identified, such as HER2, other receptor tyrosine kinases, and components of the PI3K/AKT/mTOR and Raf/MEK/ERK pathways. 31 , 32 In the current study, H19 overexpression may be related to the poor prognosis of tamoxifen-resistance breast cancer.…”

Section: Discussionmentioning

confidence: 99%

Long noncoding RNA H19 mediated the chemosensitivity of breast cancer cells via Wnt pathway and EMT process

Gao

Hao

Sun³

et al. 2018

OTT

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BackgroundBreast cancer is still one of the major public health burdens worldwide, although there is tremendous progress in early diagnosis and treatment of breast cancer. Tamoxifen was one of the most popular endocrine therapies for early-stage estrogen receptor (ER) + breast cancer patients. However, a high incidence of drug resistance develops along with poor prognosis in breast cancer. Currently, long noncoding RNAs (lncRNAs) are emerging and are well suited to play a role in the development of cancer and tamoxifen resistance. However, there is little reported about the relationship of breast cancer resistance to tamoxifen and lncRNA H19. Here, we validated that lncRNA H19 was highly expressed in breast cancer especially in patients with late stage (III and IV), compared to normal tissues and early stage cancers (I and II).MethodsQuantitative polymerase chain reaction (qPCR) was utilized for comparison of lncRNA H19 expression level in breast cancers with different stages. qPCR and Western blotting were used to detect gene and protein, respectively.ResultsWe found that lncRNA H19 expression level manipulated breast cancer cell proliferation both in parental breast cancer cell lines and tamoxifen-resistant cell lines. Knockdown of lncRNA H19 elevated tamoxifen sensitivity for promoting cell growth and inhibiting apoptosis in tamoxifen-resistant breast cancer cells. Moreover, knockdown of H19 inhibited Wnt pathway and epithelia–mesenchymal transition in tamoxifen-resistance breast cancer cells.ConclusionTaken together, the results of this study provided the evidence for H19 in regulating tamoxifen-resistant breast cancer and might provide novel options in the future treatment of tamoxifen-resistance breast cancer patients.

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“…SASP gene-upregulation by PRC2 inhibition is independent of p16 CDKN2A/p16 was considered a critical PRC2 target for proliferation blockage upon PRC2 inhibition in many cancers including nasopharyngeal carcer, breast cancer, leukemia, and ovarian cancer [44][45][46][47]. However, the requirement of p16 in these circumstances has not been studied yet.…”

Section: Prc2 Inhibition Induces Multiple Features Of Cellular Senesc...mentioning

confidence: 99%

Induction of senescence-associated secretory phenotype underlies the therapeutic efficacy of PRC2 inhibition in cancer

Chu

et al. 2022

Cell Death Dis

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The methyltransferase Polycomb Repressive Complex 2 (PRC2), composed of EZH2, SUZ12, and EED subunits, is associated with transcriptional repression via tri-methylation of histone H3 on lysine 27 residue (H3K27me3). PRC2 is a valid drug target, as the EZH2 gain-of-function mutations identified in patient samples drive tumorigenesis. PRC2 inhibitors have been discovered and demonstrated anti-cancer efficacy in clinic. However, their pharmacological mechanisms are poorly understood. MAK683 is a potent EED inhibitor in clinical development. Focusing on MAK683-sensitive tumors with SMARCB1 or ARID1A loss, we identified a group of PRC2 target genes with high H3K27me3 signal through epigenomic and transcriptomic analysis. Multiple senescence-associated secretory phenotype (SASP) genes, such as GATA4, MMP2/10, ITGA2 and GBP1, are in this group besides previously identified CDKN2A/p16. Upon PRC2 inhibition, the de-repression of SASP genes is detected in multiple sensitive models and contributes to decreased Ki67+, extracellular matrix (ECM) reorganization, senescence associated inflammation and tumor regression even in CDKN2A/p16 knockout tumor. And the combination of PRC2 inhibitor and CDK4/6 inhibitor leads to better effect. The genes potential regulated by PRC2 in neuroblastoma samples exhibited significant enrichment of ECM and senescence associated inflammation, supporting the clinical relevance of our results. Altogether, our results unravel the pharmacological mechanism of PRC2 inhibitors and propose a combination strategy for MAK683 and other PRC2 drugs.

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EZH2 inhibition sensitizes tamoxifen‑resistant breast cancer cells through cell cycle regulation

Cited by 8 publications

References 45 publications

SMYD2 aggravates gastrointestinal stromal tumor via upregulation of EZH2 and downregulation of TET1

SMYD2 aggravates gastrointestinal stromal tumor via upregulation of EZH2 and downregulation of TET1

Long noncoding RNA H19 mediated the chemosensitivity of breast cancer cells via Wnt pathway and EMT process

Induction of senescence-associated secretory phenotype underlies the therapeutic efficacy of PRC2 inhibition in cancer

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