Although autophagy

has been reported to paradoxically promote cell survival and death during tumor development and in cancer therapy,27 our results demonstrate that HDAC6 functions as a tumor suppressor by activating autophagic cell death in liver cancer. Earlier studies on the mechanism underlying the regulation of autophagy in cancer cells showed that autophagy is regulated by multiple diverse signaling pathways, such as the class II PI3K, the protein kinase mammalian target of rapamycin (mTOR), extracellular signal-regulated kinase (ERK), and the p38 pathways.26 In this regard, we noted with interest a report that the activation of JNK can mediate Beclin 1 expression, which see more is known to play a key role in the autophagic cell death of cancer cells.21 Concordantly, Beclin 1 expression was found to be induced

in mouse xenograft tumor tissues injected with HDAC6-overexpressing Hep3B cells (Fig. 6F). It was also found that sustained expression of HDAC6 induced Beclin 1 expression, whereas its resilencing suppressed Beclin 1 induction and autophagy, as determined by reduced LC3B-II conversion in Hep3B_HDAC6 Clone #1 and Clone #2 cells (Fig. 7A,B). AT9283 mouse Thus, we postulated that HDAC6 could activate the JNK pathway and mediate Beclin 1-dependent autophagy in liver cancer cells. To clarify this hypothesis, we focused on the relationships between JNK pathway activation and Beclin 1 expression in HDAC6-induced autophagy, and demonstrated that during HDAC6-induced autophagy the JNK pathway is activated in liver cancer cell lines, and that this induced Beclin 1 expression. On the other hand, the JNK-specific inhibitor SP600125 and HDAC6 knockdown inhibited Beclin 1 induction and autophagy activation (Fig. 8). Moreover, we observed that c-Jun was also involved

in the regulation of Beclin 1 in response to HDAC6-induced autophagy. These results suggest a novel mechanism for the regulation of Beclin 1 expression in HDAC6-induced autophagy in liver cancer. Although it is not clear whether HDAC6 directly activates JNK/c-Jun signaling, it is obvious that selleck HDAC6 causes autophagic cell death by way of JNK-mediated Beclin 1 expression in liver cancer cells. Taken together, the present study shows that HDAC6 expression is suppressed or lost in HCC, and that the ectopic expression of HDAC6 inhibits in vitro and in vivo tumor growth by promoting autophagic cell death and by activating a JNK-mediated Beclin 1 pathway. Future detailed analyses of the molecular mechanisms governing HDAC6 inactivation should illustrate how HDAC6 influences the balance of autophagic signals. Here, we propose for the first time that HDAC6 functions as a tumor suppressor by activating caspase-independent autophagic cell death during hepatocarcinogenesis, and thus, our findings might support the clinical potential of HDAC6 for the treatment of liver cancer.