Recently, high expression of HDACs, in particular HDAC6, has been observed in tumor samples of HCC patient, and a few HDAC inhibitors, including FDA-approved suberoylanilide hydroxamic acid (SAHA), display potent antitumor effect on HCC.
Intriguingly, HDAC6-depleted T cells triggers PD-1-PD-L1 expression to achieve a strong synergistic effect to sensitize advanced HCC to immune checkpoint blocker, while blockade of IL-17A partially suppresses it.
Furthermore, we demonstrated that recovery of HDAC6 elicited let-7i-5p suppression to de-repress TSP1 expression; therefore, it occupied the CD47 receptor to block CD47-SIRPα-mediated anti-phagocytosis of macrophage in HCC.
These results demonstrated that HDAC6 functioned as a tumor suppressor in HCC by attenuating the activity of the canonical Wnt/β-catenin signaling pathway.
HDAC6 may serve as a recurrence predictive factor for HCC after LT and pharmacological or genetic activation of HDAC6 could be a novel anti-angiogenesis approach for HCC therapy.
Our findings suggest that loss of HDAC6 expression in human HCCs and tumor suppression by HDAC6 occur by way of activation of caspase-independent autophagic cell death through the JNK/Beclin 1 pathway in liver cancer and, thus, that a novel tumor suppressor function mechanism involving HDAC6 may be amenable to nonepigenetic regulation.
Overexpression of HDAC6 protein to a level higher than that in the corresponding normal hepatocytes was observed in 14 (20%) of the 70 primary HCCs, and was significantly correlated with high clinical stage, number of tumors, vascular invasion and intrahepatic metastasis (P<0.05).