Histone deacetylase 6-EGFR axis in recurrent hepatocellular carcinoma

• Published in: Journal of clinical oncology Vol. 37; no. 15_suppl; p. e15638
• Main Authors: Yeh, Yao-Tsung, Dai, Hong-Ying, Wang, Shen-Nien, Chang-Chien, Pin-Jou
• Format: Journal Article
• Language: English
• Published: 20.05.2019
• ISSN: 0732-183X; 1527-7755
• DOI: 10.1200/JCO.2019.37.15_suppl.e15638

Abstract only e15638 Background: Alterations of histone deacetylases (HDACs) and related signaling have been increasingly associated with cancer development and treatment. Among those HDACs, HDAC6 uniquely functions in maintaining mRNA stability of certain genes. The aim of this study was to determine the clinical impacts and associated mechanisms of HDAC6 in hepatocellular carcinoma (HCC). Methods: Immunohistochemistry is firstly applied to analyze the distribution patterns of HDAC6 in 122 patients and the obtained results are statistically analyzed with clinicopathological characteristics and patient survival. XTT, flowcytometery, transwell assay, real-time PCR, IF, IB, immunoprecipitation (IP), and RNA-IP are used to determine the bio-impacts and underlying mechanisms of HDAC6 in liver cancer cells. Results: Both cytoplasmic and nuclear staining of HDAC6 proteins were mainly decreased in cancerous lesions. Nevertheless, increased cytoplasmic HDAC6 staining was positively correlated with disease recurrence (p = 0.002). Increased nuclear frequency, but not cytoplasmic intensity, of HDAC6 was associated with a poor survival rate in HCC patients (p = 0.041). Restoration of HDAC6 expression increased the proliferation, S phase, migration and invasion of the HepJ5, Huh7 and Mahlavu cells, lacking detectable HDAC6 expression. More interestingly, ectopic HDAC6 overexpression increased a ligand-independent expression of p-AKT, beta-catenin and cyclin D, and subsequently promoted the entry of beta-catenin into the nucleus. Both transcripts and proteins of the EGFR, a dominant trigger of AKT signaling, were unexpectedly increased upon HDAC6 restoration in HepJ5, Huh7 and Mahlavu cells. The expression of EGFR was not restored by treatment with MG132 (proteasome inhibitor) in HepJ5, Huh7 and Mahlavu cells, and HDAC6-specific siRNA decreased both HDAC6 and EGFR expression in Hep3B and SK-Hep1 cells, having detectable HDAC6 and EGFR expression. IP and RNA-IP analysis revealed that HDAC6 interacted with HuR and increased EGFR mRNA stability. Accordingly, the expression of HDAC6 and EGFR were positively correlated in cancerous lesions. Conclusions: Our results suggest that the contribution of HDAC6 to recurrent HCC may act through its maintenance of EGFR mRNA stability. HDAC6 may serve as a rational treatment target in recurrent HCC.