Epigenetics in ovarian cancer: premise, properties, and perspectives

Abstract

Malignant ovarian tumors bear the highest mortality rate among all gynecological cancers. Both late tumor diagnosis and tolerance to available chemical therapy increase patient mortality. Therefore, it is both urgent and important to identify biomarkers facilitating early identification and novel agents preventing recurrence. Accumulating evidence demonstrates that epigenetic aberrations (particularly histone modifications) are crucial in tumor initiation and development. Histone acetylation and methylation are respectively regulated by acetyltransferases-deacetylases and methyltransferases-demethylases, both of which are implicated in ovarian cancer pathogenesis. In this review, we summarize the most recent discoveries pertaining to ovarian cancer development arising from the imbalance of histone acetylation and methylation, and provide insight into novel therapeutic interventions for the treatment of ovarian carcinoma.

Keywords: Epigenetics; Histone acetylation; Histone methylaiton; Ovarian cancer.

Fig. 1

A schematic mechanism of histone acetylation and methylation. The balance of histone acetylation and methylation is respectively controlled by histone acetyltransferases-deacetylases and histone methyltransferases-demethylases. Acetylation of histone tails is associated with a relaxed chromatin structure and transcriptional activation. Conversely, methylation of histone tails is linked with a condensed chromatin structure and transcriptional suppression. Disruption of the steady state of histone acetylation and methylation may cause abnormal cellular function, possibly even ovarian cancer

Fig. 2

a Type A HAT families. AT: acetyltransferase domain; Zn: Zic finger domain; Bromo: bromodomain. GNAT domain includes three key motifs and these motifs in structure is in this order: D-A-B. Some of GNAT family members contain another conserved motif C that is located at the N-terminus of these proteins. b Topological diagram of the core GNAT fold. The highly conserved GNAT domain composed of 6–7 anti-parallel β-strands and 4 α-helices in the topology β1-α1-α2-β2-β3-β4-α3-β5-α4-β6-β7. Motifs A and B participate in acyl-CoA and acceptor substrate recognition and binding, and the feature of motif A is the “P-loop” that connect helix α3 and strand β4. Motifs C and D preserve the stability of proteins

Fig. 3

HDAC families and their domain structure

Fig. 4

A series of targets of SIRT1, and its multiple pathways that contribute to ovarian cancer. SIRT1 deacetylases both histones and non-histones. SIRT1 could directly decrease the degree of acetylation of histone H1K26, H3K9, H3K14, and H4K16, and also indirectly regulate the methylation and acetylation of histone by interacting with other histone-modifying enzymes such as SUV39H1, P300, PCAF, and Tip60. The non-histone substrates of SIRT1 (transcriptional factors, DNA repair machinery elements, nuclear receptor genes, and signaling molecules) are critical in the initiation and progression of ovarian cancer

Fig. 5

Histone lysine methyltransferases(HKMTs): classfication, histone targets, primary domain architecture. HKMTs are classified in two types: the SET domain-containing proteins and the DOT1-like proteins. The SET domain-containing proteins can be subdivided into four families by structural sequence features: SUV39, SET1, SET2 and RIZ. Except for these family listed above, there are other SET domain -containing methyltransferases that have not been classfied into a specific group, for instance, SET8, SET7/9, SMYD subfamily and SUV4–20 subfamily

Fig. 6

The structure and function of EZH2. a. The schematic view of EZH2 principal domain; b. Four core subunits of PRC2; c. The schematic illustration of EZH2 function in ovarian cancer