J Pathol Transl Med.  2016 Sep;50(5):337-344. 10.4132/jptm.2016.05.20.

SIRT7, H3K18ac, and ELK4 Immunohistochemical Expression in Hepatocellular Carcinoma

• Lee HS
• Jung W
• Lee E
• Chang H
• Choi JH
• Kim HG
• Kim A
• Kim BH

• KMID: 2353595
• DOI: http://doi.org/10.4132/jptm.2016.05.20

Abstract

BACKGROUND
SIRT7 is one of the histone deacetylases and is NAD-dependent. It forms a complex with ETS-like transcription factor 4 (ELK4), which deacetylates H3K18ac and works as a transcriptional suppressor. Overexpression of SIRT7 and deacetylation of H3K18ac have been shown to be associated with aggressive clinical behavior in some cancers, including hepatocellular carcinoma (HCC). The present study investigated the immunohistochemical expression of SIRT7, H3K18ac, and ELK4 in hepatocellular carcinoma.
METHODS
A total of 278 HCC patients were enrolled in this study. Tissue microarray blocks were made from existing paraffin-embedded blocks. Immunohistochemical expressions of SIRT7, H3K18ac and ELK4 were scored and analyzed.
RESULTS
High SIRT7 (p = .034), high H3K18ac (p = .001), and low ELK4 (p = .021) groups were associated with poor outcomes. Age < 65 years (p = .028), tumor size ≥ 5 cm (p = .001), presence of vascular emboli (p = .003), involvement of surgical margin (p = .001), and high American Joint Committee on Cancer stage (III&V) (p < .001) were correlated with worse prognoses. In multivariate analysis, H3K18ac (p = .001) and ELK4 (p = .015) were the significant independent prognostic factors.
CONCLUSIONS
High SIRT7 expression with poor overall survival implies that deacetylation of H3K18ac contributes to progression of HCC. High H3K18ac expression with poor prognosis is predicted due to a compensation mechanism. In addition, high ELK4 expression with good prognosis suggests another role of ELK4 as a tumor suppressor beyond SIRT7's helper. In conclusion, we could assume that the H3K18ac deacetylation pathway is influenced by many other factors.

Keyword

Carcinoma, hepatocellular; ELK4; Sirtuin 7 protein; H3K18ac; Immunohistochemistry

MeSH Terms

Carcinoma, Hepatocellular*
Compensation and Redress
Histone Deacetylases
Humans
Immunohistochemistry
Joints
Multivariate Analysis
Prognosis
Transcription Factors
Histone Deacetylases
Transcription Factors

Figure

• 

  Fig. 1. Characteristic nuclear staining of tumor cells by immunohistochemistry. Low SIRT7 expression (A), high SIRT7 expression (B), low H3K18ac expression (C), high H3K18ac expression (D), low ELK4 expression (E), and high ELK4 expression (F) are seen.

• 

  Fig. 2. Kaplan-Meier survival curves of immunohistochemical (IHC) markers and clinicopathologic data. With IHC markers (A–C), high SIRT7 expression (A) and high H3K18ac expression (B) were associated with poor prognosis (p = .034 and p = .001, respectively). However, high ETS-like transcription factor 4 (ELK4) expression was associated with good prognosis (p = .021) (C). With clinicopathologic factors (D–F), high American Joint Committee on Cancer stage (III, IV) (p < .001) (D), large tumor size (maximal diameter ≥ 5 cm) (p = .001) (E), and the presence of vascular emboli (F) were associated with poor overall survival (p = .003).

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