SETD6 controls the expression of estrogen-responsive genes and proliferation of breast carcinoma cells

O’Neill, Daniel; Williamson, Stuart C.; Alkharaif, Dhuha; Monteiro, Isabella Christina Mazzaro; Goudreault, Marilyn; Gaughan, Luke; Robson, Craig; Gingras, Anne‐Claude; Binda, Olivier

doi:10.4161/epi.28864

Cited by 30 publications

(28 citation statements)

References 51 publications

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“…Very little is known about the remaining SET proteins, although amplification of ASH1L was recently reported in over 10% of breast cancers (Liu et al., 2015). Intriguingly, knockdown of both SETD4 (Faria et al., 2013) and SETD6 (O'Neill et al., 2014) significantly suppressed proliferation of breast cancer cell lines, suggesting they may have pro‐proliferative functions.…”

Section: Introductionmentioning

confidence: 99%

Dysregulation of histone methyltransferases in breast cancer – Opportunities for new targeted therapies?

Michalak

Visvader

2016

Molecular Oncology

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Histone methyltransferases (HMTs) catalyze the methylation of lysine and arginine residues on histone tails and non-histone targets. These important post-translational modifications are exquisitely regulated and affect chromatin compaction and transcriptional programs leading to diverse biological outcomes. There is accumulating evidence that genetic alterations of several HMTs impinge on oncogenic or tumor-suppressor functions and influence both cancer initiation and progression. HMTs therefore represent an opportunity for therapeutic targeting in those patients with tumors in which HMTs are dysregulated, to reverse the histone marks and transcriptional programs associated with aggressive tumor behavior. In this review, we describe the known histone methyltransferases and their emerging roles in breast cancer tumorigenesis.

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Section: Introductionmentioning

confidence: 99%

Dysregulation of histone methyltransferases in breast cancer – Opportunities for new targeted therapies?

Michalak

Visvader

2016

Molecular Oncology

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“…Lysine methylation, catalyzed by protein lysine methyltransferases (PKMTs), is a PTM that plays a key role in a variety of essential cellular signaling pathways (14). In recent years, the PKMT SETD6 has been shown to participate in the NF-κB cascade (15,16), the nuclear factor erythroid 2-related factor 2 (NRF2) oxidative stress response (17), the Wnt signaling pathway (18), nuclear hormone receptor signaling (19), and embryonic stem cell differentiation (20), all of which are vital cellular processes.…”

mentioning

confidence: 99%

The methyltransferase SETD6 regulates Mitotic progression through PLK1 methylation

Feldman

Vershinin

Goliand

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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Lysine methylation, catalyzed by protein lysine methyltransferases (PKMTs), is a key player in regulating intracellular signaling pathways. However, the role of PKMTs and the methylation of nonhistone proteins during the cell cycle are largely unexplored. In a recent proteomic screen, we identified that the PKMT SETD6 methylates PLK1—a key regulator of mitosis and highly expressed in tumor cells. In this study, we provide evidence that SETD6 is involved in cell cycle regulation. SETD6-deficient cells were observed to progress faster through the different mitotic steps toward the cytokinesis stage. Mechanistically, we found that during mitosis SETD6 binds and methylates PLK1 on two lysine residues: K209 and K413. Lack of methylation of these two residues results in increased kinase activity of PLK1, leading to accelerated mitosis and faster cellular proliferation, similarly to SETD6-deficient cells. Taken together, our findings reveal a role for SETD6 in regulating mitotic progression, suggesting a pathway through which SETD6 methylation activity contributes to normal mitotic pace.

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“…SETD6 is a mono-methyltransferase that directly methylates RelA at Lys-310 to suppress the activation of NF-B target genes. It was recently shown that mono-methylation of H2AZ by SETD6 at lysine 7 is required for the maintenance of embryonic stem cell self-renewal (11) and that SETD6 associates with several factors that control the expression of estrogenresponsive genes in the nuclear hormone receptor signaling pathway (12).…”

mentioning

confidence: 99%

PAK4 Methylation by SETD6 Promotes the Activation of the Wnt/β-Catenin Pathway

Vershinin

Feldman

Chen

et al. 2016

Journal of Biological Chemistry

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Lysine methylation of non-histone proteins has emerged as a key regulator of many cellular functions. Although less studied than other post-translational modifications such as phosphorylation and acetylation, the number of known methylated nonhistone proteins is rapidly expanding. We have identified the p21-activated kinase 4 (PAK4) as a new substrate for methylation by the protein lysine methyltransferase SETD6. Our data demonstrate that SETD6 methylates PAK4 both in vitro and at chromatin in cells. Interestingly, depletion of SETD6 in various cellular systems significantly hinders the activation of the Wnt/ ␤-catenin target genes. PAK4 was recently shown to regulate ␤-catenin signaling, and we show that SETD6 is a key mediator of this pathway. In the presence of SETD6, the physical interaction between PAK4 and ␤-catenin is dramatically increased, leading to a significant increase in the transcription of ␤-catenin target genes. Taken together, our results uncover a new regulatory layer of the Wnt/␤-catenin signaling cascade and provide new insight into SETD6 biology.

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SETD6 controls the expression of estrogen-responsive genes and proliferation of breast carcinoma cells

Cited by 30 publications

References 51 publications

Dysregulation of histone methyltransferases in breast cancer – Opportunities for new targeted therapies?

Dysregulation of histone methyltransferases in breast cancer – Opportunities for new targeted therapies?

The methyltransferase SETD6 regulates Mitotic progression through PLK1 methylation

PAK4 Methylation by SETD6 Promotes the Activation of the Wnt/β-Catenin Pathway

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