SET Domain–Containing Protein 4 Epigenetically Controls Breast Cancer Stem Cell Quiescence

Ye, Sen; Ding, Yan-Fu; Jia, Wen-Huan; Liu, Xiaoli; Feng, Jingyi; Zhu, Qian; Cai, Sun-Li; Yang, Yao-Shun; Lu, Qian-Yun; Huang, Xue-Ting; Yang, Jin‐Shu; Jia, Shengnan; Ding, Guoping; Wang, Yuehong; Zhou, Jiaojiao; Chen, Yiding; Yang, Wei‐Jun

doi:10.1158/0008-5472.can-19-1084

Cited by 45 publications

(44 citation statements)

References 48 publications

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“…Our current results suggest SETD4 deficiency leads to BMSCs proliferation without affecting the apoptosis. Very recently, Ye S and colleagues reported SETD4 overexpressed breast cancer stem cells deserved low Ki67 expression when compared with SETD4 low expressed breast cancer stem cells; they concluded SETD4 controls breast cancer stem cell quiescence [6]. Our current research found that SETD4 KO BMSCs retain high cell proliferative potentials, which is consistent with Ye S's report on cell proliferation characteristics.…”

Section: Discussionsupporting

confidence: 90%

“…SET domain-containing protein 4 (STED4) is a number of SET gene families that process histone and non-histone methyltransferase activity. Previous reports have revealed that SETD4 over-expression controls cancer cell proliferation [4,5] and the cell quiescence via H4K20me3 catalysis [6,7]. Very recently, SETD4-catalyzed H3K4me1 and H3K4me2 were also documented to be closely associated with the release of inflammatory cytokines in macrophage [8].…”

Section: Introductionmentioning

confidence: 98%

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SET domain-containing protein 4: biological functions and role in genomic methylation profiles of bone marrow mesenchymal stem cells

Liao

Shao

et al. 2020

Preprint

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Background: Epigenetic modification is a crucial mechanism affecting the biological function of stem cells. SETD4 is a histone methyltransferase, and its biological role in bone marrow mesenchymal stem cells (BMSCs) is currently unknown. This work was aimed to reveal the SETD4 biological role as well as its impacts on the genomic methylation profiles in BMSCs. Methods: BMSCs were isolated form SETD4 knockout (KO) and wild type (WT) mice that established by CRISPR/Cas9 technology. The cell proliferation, migration, myogenic differentiation and angiogenesis were tested according to appropriate biology techniques. And the Reduced Representation Bisulfite Sequencing (RRBS) method was adopted to analyze the global genomic methylation profiles of BMSCs, following bioinformatics analysis of GO functions and KEGG signaling of differential methylated CpG sites and differential methylation regions (DMRs). Finally, validation experiments were conducted to examine the expression of histone lysine methyltransferase and some representative genes. Results: SETD4 KO significantly promoted BMSCs proliferation, which was characterized by enhanced cell viability and increased expression of PCNA, Cyclin A2, Cyclin E1, CDK2, CDK6, Bcl2 and decreased the expression of P16, P21 and Caspase3. SETD4 deficiency impaired BMSCs migration and myogenic differentiation potentials, and even the angiogenesis via paracrine of VEGF. Compared with WT control, the overall genomic methylation of BMSCs in the SETD4 KO group only was decreased by 0.47%. However, the changed genomic methylation covers a total of 96,331 differential methylated CpG sites and 8692 DMR, with part of them settled in promoter regions. GO and KEGG analysis revealed that differential CpG islands and DMRs in promotes impacted 270 GO functions and 34 KEGG signaling pathways, with some closely related to stem cell biology. SETD4 KO inhibited sets of monomethylases and dimethylases for histone lysine, along with significant changes in some factors including Nkx2.5, Gata4, Gli2, Grem2, E2f7, Map7, Nr2f2 and Shox2 that associated with stem cell biology. Conclusions: These results are the first to reveal that even though SETD4 changes the genome’s overall methylation to a limited extent in BMSCs, it still affects the numerous cellular functions and signaling pathways, implying SETD4-altered genomic methylation serves a crucial molecular role in BMSCs’ biological functions.

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Section: Discussionsupporting

confidence: 90%

Section: Introductionmentioning

confidence: 98%

SET domain-containing protein 4: biological functions and role in genomic methylation profiles of bone marrow mesenchymal stem cells

Liao

Shao

et al. 2020

Preprint

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“…By isolating BCSCs based on high flavin content, energetic BCSCs (e-BCSCs) were identified with a higher glycolytic activity and a larger mitochondrial mass (25). On the contrary, quiescent BCSCs (qBCSCs) have been reported based on the epigenetic activities (26). Mesenchymal and epithelial phenotypes of heterogeneous BCSCs have been described contributing to differential chemoresistance (27).…”

Section: Heterogeneity In Bc and Its Influence On Clinical Outcomementioning

confidence: 99%

Novel and Alternative Targets Against Breast Cancer Stemness to Combat Chemoresistance

et al. 2019

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Breast cancer stem cells (BCSCs) play a vital role in tumor progression and metastasis. They are heterogeneous and inherently radio- and chemoresistant. They have the ability to self-renew and differentiate into non-BCSCs. These determinants of BCSCs including the plasticity between the mesenchymal and epithelial phenotypes often leads to minimal residual disease (MRD), tumor relapse, and therapy failure. By studying the resistance mechanisms in BCSCs, a combinatorial therapy can be formulated to co-target BCSCs and bulk tumor cells. This review addresses breast cancer stemness and molecular underpinnings of how the cancer stemness can lead to pharmacological resistance. This might occur through rewiring of signaling pathways and modulated expression of various targets that support survival and self-renewal, clonogenicity, and multi-lineage differentiation into heterogeneous bulk tumor cells following chemotherapy. We explore emerging novel and alternative molecular targets against BC stemness and chemoresistance involving survival, drug efflux, metabolism, proliferation, cell migration, invasion, and metastasis. Strategic targeting of such vulnerabilities in BCSCs may overcome the chemoresistance and increase the longevity of the metastatic breast cancer patients.

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“…The brine shrimp Artemia Parthenogenetica SETD4 was initially suggested to play a role in methylating histone H4K20 and H3K79 (21), and the human SETD4 protein may have the same activity (35). However, another report failed to identify these sites as SETD4 substrates, and instead suggested H3K4 as the substrate of SETD4 in macrophages (36).…”

Section: Introductionmentioning

confidence: 99%

“…According to the TCGA database, oncogenic fusion of SETD4 was found to be with TMPRSS2 in prostate cancer, with FTCD in invasive ductal carcinoma, with KIAA1958 in serous ovarian cancer, and with B4Galt6 in lung squamous cancer. SETD4 was highly expressed in the quiescent breast cancer stem cell subpopulation of MCF7 cells (35), and an induced Setd4 deletion in adult mice delayed the radiationinduced T-lymphoma development in mice (40).…”

Section: Introductionmentioning

confidence: 99%

Deletion of mouseSetd4promotes the recovery of hematopoietic failure

Feng

Yue

et al. 2019

Preprint

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Key points:• Deletion of Setd4 in adult mice improved the survival from hematopoietic failure.• Setd4 deficiency sensitized HSCs to radiation, but improved bone marrow environment niche.• The study suggests that SETD4 as a potential inhibitory target to improve bone marrow niche function for recovery of bone marrow failure.Abstract: Acquired hematopoietic failure is commonly caused by therapeutic and accidental exposure to toxic agents to the bone marrow (BM). Efficient recovery from the BM failure is not only dictated by the intrinsic sensitivity and proliferation capacity of the hematopoietic stem and progenitor cells, but also nourished by the BM environment niche. Identification of genetic factors that improve the recovery from hematopoietic failure is essential. Vertebrate SETD4 is a poorly characterized, putative non-histone methyl-transferase whose physiological substrates have not yet been fully identified. By inducing Setd4 deletion in adult mice, we found that loss of Setd4 improved the survival of whole body irradiation induced BM failure. This was associated with improved recoveries of long-term and short-term hematopoietic stem cells (HSC), and early progenitor cells. BM transplantation analyses surprisingly showed that the improved recovery was not due to a radiation resistance of the Setd4 deficient HSC, but that Setd4 deficient HSC were actually more sensitive to radiation. However, the Setd4 deficient mice were better recipients for allogeneic HSC transplantation. Furthermore, there was an enhanced splenic erythropoiesis in Setd4 deficient mice. These findings not only revealed a previously unrecognized role of the Setd4 as a unique modulator of hematopoiesis, but also underscored the critical role of the BM niche in the recovery of hematopoietic failure. These studies also implicated Setd4 as a potential target for therapeutic inhibition to improve the conditioning of the BM niche prior to allogeneic transplantation. Authorship Contributions: XF and ZS: designed the experiments, performed data analysis, and drafted the initial versions of manuscript. XF: performed most of the experiments; HL, JL, and MS: performed and assisted with some of the experiments. HL, and JY: performed some of the early studies led to the construction of the mouse models; LD, and SD: provided resources for some experiments, computational analysis, and edited the manuscript. ZS: directed and oversaw the project, secured funding for the study, completed the final version of the manuscript. Conflict of Interest statement:The authors declare that there were no competing interests.

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SET Domain–Containing Protein 4 Epigenetically Controls Breast Cancer Stem Cell Quiescence

Cited by 45 publications

References 48 publications

SET domain-containing protein 4: biological functions and role in genomic methylation profiles of bone marrow mesenchymal stem cells

SET domain-containing protein 4: biological functions and role in genomic methylation profiles of bone marrow mesenchymal stem cells

Novel and Alternative Targets Against Breast Cancer Stemness to Combat Chemoresistance

Deletion of mouseSetd4promotes the recovery of hematopoietic failure

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