A three layered histone epigenetics in breast cancer metastasis

Abstract

Thanks to the advancement in science and technology and a significant number of cancer research programs being carried out throughout the world, the prevention, prognosis and treatment of breast cancer are improving with a positive and steady pace. However, a stern thoughtful attention is required for the metastatic breast cancer cases-the deadliest of all types of breast cancer, with a character of relapse even when treated. In an effort to explore the less travelled avenues, we summarize here studies underlying the aspects of histone epigenetics in breast cancer metastasis. Authoritative reviews on breast cancer epigenetics are already available; however, there is an urgent need to focus on the epigenetics involved in metastatic character of this cancer. Here we put forward a comprehensive review on how different layers of histone epigenetics comprising of histone chaperones, histone variants and histone modifications interplay to create breast cancer metastasis landscape. Finally, we propose a hypothesis of integrating histone-epigenetic factors as biomarkers that encompass different breast cancer subtypes and hence could be exploited as a target of larger population.

Keywords: Breast cancer; Chaperone; Histone; Metastasis; Modification; Variants.

Fig. 1

Layers of histone epigenetics composed of histone chaperones, histone variants and their modifications. (1) First layer of histone epigenetics is histone chaperone, which recruits histone variants into the chromatin. Canonical histones are recruited in replication dependent manner while non-canonical histone variants are recruited in replication independent manner. (2) Second layer of histone epigenetics is histone variants, which plays an important role of maintaining chromatin switch [ON/OFF state]. (3) Final layer of histone epigenetics is Histone Modifications which further modifies the chromatin state by addition of functional groups into the tails of histones

Fig. 2

Histone chaperone landscape of breast cancer metastasis. (1) APLF downregulation causes recruitment of repressive histone MacroH2A.1 in the promoter of mesenchymal genes like SNAI1, SNAI2 and MMPs, thereby promoting MET. Another pathway by APLF is showing, how repressive histone mark EZH2/H3K27me3 is recruited in the promoter region of FOXA1. In absence of FOXA1, CDH1 stops transcribing, thus pushing the cell towards EMT. (2) In ANP32E over-expressed cells, cell cycle regulator E2F1 causes upregulation of Cyclin E1/E2 therefore leading the cells to cell cycle. However, ANP32E itself is regulated at the transcript level by mi-RNA-141. (3) Over-expression of FACT has been associated with Breast Cancer Metastasis. (4) DEK has been found to directly inhibit CDH1, thus causing EMT. DEK also promotes angiogenesis by binding to DRE (DEK Response Element) in the VEGF promoter and recruiting p300 and HIF-α. Another pathway is showing how DEK induces metastasis via PI3K/AKT/mTOR pathway. (5) ASF1B is found to be upregulated in breast cancer metastasis. (6) NPM1 causes c-FOS suppression via YY1 expression. NPM1 also upregulates CDH1 levels, which causes SKP2 degradation, leading to p27KIP1 ubiquitination, thereby inducing breast cancer proliferation. (7) DNA Double Strand Breaks (DSBs) causes recruitment of ATM, which phosphorylates HJURP. HJURP along with DNA repairing protein hMSH5 and NBS1 repairs the DNA. (8) DAXXX inhibits c-MET [proto-oncogene] directly as well as via HDAC2 recruitment. DAXX binds to the promoter region of RAD-51 and forms repressive mark. However in breast cancer metastasis, downregulation of DAXX is found which causes over-expression of RAD-51 and the entire process corroborates the metastatic phenomenon

Fig. 3

Histone variants in the regulation of cell cycle in breast cancer. a Enrichment of H2A.Z in the c-MYCpromoter induces c-Myc expression. c-MYC in turn inhibits p21 [cell cycle inhibitor] thereby leading the cells into cell cycle. H2A.Z also causes p21/p51 transcriptional repression by binding to the later’s promoter region. H2A.Z knockdown induce EMT in MCF-10A. b (i) MacroH2A.2 recruits EZH2 which causes H3K27me3 repressive mark in the promoter region of LOX gene. LOX causes change in the αvβ₃ integrin which causes phosphorylation of c-SRC causing cytoskeleton and ECM remodeling and finally leading to breast cancer bone metastasis. b (ii) SCF SKP2 causes ubiquitination and degradation of MacroH2A1, leading to CDK8 upregulation followed by Cyclin A/CDK2 recruitment, which causes cell proliferation. Besides, SCF SKP2, CDK8 and Cyclin A/CDK2 also ubiquitinates cell cycle inhibitor p27