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To the Editor:

We read with great interest the article by Zhang et al.1 in which the authors demonstrate that pharmacological targeting of the chromatin remodeling enzymes histone deacetylases (HDAC) and poly (ADP-ribose) polymerases inhibit hepatocellular carcinoma (HCC) cell growth. The authors showed that HCC cells display differential sensitivity to the HDAC inhibitor SAHA and PARP inhibitor olaparib, and identified two cell lines with sensitive versus resistant phenotype to both enzyme inhibitors, respectively. Moreover, using these compounds they extensively characterize the signaling pathway involved in the repair of DNA strand breaks and in cell survival. Although these findings suggest that combination therapy with both SAHA and olaparib inhibitors may be a strategy for therapy of sensitive HCC cells, there are some aspects that I believe need to be stressed. Poly ADP ribosylation by PARP is indispensable for recruitment and activation of ATP-dependent chromatin remodeler ALC1 (amplified in liver cancer 1).2 ALC1 is an important oncogene implicated in the pathogenesis of HCC. Aberrant amplification/overexpression of ALC1 is present in about 50% of all HCC cases and ALC1-overexpressing cells exhibit increased colony formation in soft agar and increased tumorigenicity in nude mice.3 HepG2, shown by Zhang et al.1 to be the most responsive cell line to SAHA and olaparib, display much higher ALC1 expression than human HCC tissue.3 It would be interesting to see if the two cell lines described by Zhang et al. express ALC1 and at which levels, and to what extent findings with olaparib are exploitable by clinics in the half of HCC cases that are ALC1 negative. SAHA is an effective inhibitor of HCC growth. Nonetheless, liver-specific inhibition of SAHA-targeted class I HDAC3 gene causes steatosis and disruption of circadian rhythms in normal liver parenchyma by impinging on multiple signaling pathways in mice.4 Without well-designed in vivo studies it will be hard to assess the efficacy of epigenetic combinatorial HCC therapy and the effects of these drugs on healthy surrounding liver tissue.

References

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  • 1
    Zhang JX, Li DQ, He AR, Motwani M, Vasiliou V, Eswaran J, et al. Synergistic inhibition of hepatocellular carcinoma growth by cotargeting chromatin modifying enzymes and poly (ADP-ribose) polymerases. HEPATOLOGY 2012; 55: 1840-1851.
  • 2
    Gottschalk AJ, Timinszky G, Kong SE, Jin J, Cai Y, Swanson SK, et al. Poly(ADP-ribosyl)ation directs recruitment and activation of an ATP-dependent chromatin remodeler. Proc Natl Acad Sci U S A 2009; 106: 13770-13774.
  • 3
    Ma NF, Hu L, Fung JM, Xie D, Zheng BJ, Chen L, et al. Isolation and characterization of a novel oncogene, amplified in liver cancer 1, within a commonly amplified region at 1q21 in hepatocellular carcinoma. HEPATOLOGY 2008; 47: 503-510.
  • 4
    Feng D, Liu T, Sun Z, Bugge A, Mullican SE, Alenghat T, et al. A circadian rhythm orchestrated by histone deacetylase 3 controls hepatic lipid metabolism. Science 2011; 331: 1315-1319.

Manlio Vinciguerra Ph.D.*, * Head of Epigenetics of Fatty Liver Diseases Unit, Institute of Hepatology, Harold Samuel House, London, UK.