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Review
. 2019 Aug 9;11(8):1143.
doi: 10.3390/cancers11081143.

SETDB-1: A Potential Epigenetic Regulator in Breast Cancer Metastasis

Jacob Batham  1 , Pek Siew Lim  2 , Sudha Rao  3
Affiliations
Review

SETDB-1: A Potential Epigenetic Regulator in Breast Cancer Metastasis

Jacob Batham et al. Cancers (Basel). .

Abstract

The full epigenetic repertoire governing breast cancer metastasis is not completely understood. Here, we discuss the histone methyltransferase SET Domain Bifurcated Histone Lysine Methyltransferase 1 (SETDB1) and its role in breast cancer metastasis. SETDB1 serves as an exemplar of the difficulties faced when developing therapies that not only specifically target cancer cells but also the more elusive and aggressive stem cells that contribute to metastasis via epithelial-to-mesenchymal transition and confer resistance to therapies.

Keywords: SETDB1; breast cancer; cancer stem cells; epigenetics; recurrence; resistance; therapy.

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Conflict of interest statement

In accordance with NHMRC guidelines and our ethical obligations as researchers, we report that P.S.L. and S.R. have a financial interest in EpiAxis Therapeutics Pty Ltd. S.R. is also a Chief Scientific Officer of EpiAxis Therapeutics Pty Ltd. We also have in place a plan for managing any potential conflicts arising from that involvement.

Figures

Figure 1
Figure 1
DNA-methyltransferase 3 A/B (DMNT-3 A/B) CpG island-mediated signaling of SET Domain Bifurcated Histone Lysine Methyltransferase 1 (SETDB1). SETDB1 methyltransferase activity is activated through signaling via DNMT-3 A/B. SETDB1 catalytically recruits S-adenosyl-homocysteine (SAH) and homolog of murine ATFa (Activating Transcription Factor a)-associated modulator (hAM) as methyl donors. Histone 3 lysine residue 9 (H3K9me) is then di- and tri-methylated, which leads to euchromatin being condensed into heterochromatin to repress transcription.
Figure 2
Figure 2
Schematic of SETDB1 domains inclusive of amino-acid location. Blue circles = Nuclear Export Sequence (NES), green circles = NLS (nuclear recognition sequences), purple square = heterochromatin protein-1 (HP-1).
Figure 3
Figure 3
SETDB1 interacts with transcriptional regulators to induce heterochromatin formation. SETDB1 tri-methylation of histone tails is a multifactorial process that requires the orchestrated recruitment and interactions of various chromatin proteins to repress transcription.
Figure 4
Figure 4
SETDB1’s influence on epithelial-to-mesenchymal transition (EMT) programs that initiate metastasis. This metabolic reprogramming altered the breast cancer phenotype and contributed to progression through acquisition of cancer stem cell characteristics.
See this image and copyright information in PMC

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