Dichloroacetate attenuates the stemness of hepatocellular carcinoma cells via promoting nucleus‐cytoplasm translocation of YAP

Abstract

The antitumor effects of dichloroacetate (DCA) have been widely explored, however, its roles in hepatocellular carcinoma (HCC) progression are still unclear. In the current work, we found that DCA had little effects on HCC cell viability, but could attenuate the stemness of HCC cells, which is evident by decreasing the tumor sphere‐formation ability, ALDH activity and the expression of stemness critical regulators. Mechanistic studies based on RNA‐sequencing data showed that DCA activated the Hippo pathway. Furthermore, we indicated that DCA promoted the nucleus‐cytoplasm translocation of YAP, but not TAZ, another critical executor of Hippo pathway. Moreover, suppressing of Hippo pathway using XMU‐MP‐1, an inhibitor of Hippo pathway, partially abrogated DCA‐induced inhibitory effects on HCC cell stemness. This work suggests that DCA might be a potential inhibitor for HCC progression.

CHRNA5 Contributes to Hepatocellular Carcinoma Progression by Regulating YAP Activity

“…YAP, playing an essential role in cancer progression, was reported to be implicated in modulating various malignant phenotypes of cancer cells, such as cell proliferation, migration, invasion, apoptosis resistance, EMT phenotype, and stemness properties [44][45][46]. In this study, data from the TCGA database exhibited a close association between CHRNA5 and the Hippo signaling pathway in HCC.…”

Targeting the Hippo/YAP/TAZ signalling pathway: Novel opportunities for therapeutic interventions into skin cancers

“…A35, a synthetic inhibitor of DNA topoisomerase II, was found to decrease YAP nuclear localization by activating its phosphorylation 190 . Likewise, dichloroacetate, a small molecule metabolic regulator used for treating mitochondrial genetic diseases and lactic acid poisoning, was shown to promote the nuclear‐cytoplasmic translocation of YAP 191 . However, as in the case of verteporfin, the reported anti‐tumour effects of these compounds are likely not YAP/TAZ‐specific.…”

An Updated Understanding of the Role of YAP in Driving Oncogenic Responses

“…For example, A35, a novel synthetic cyclizing berberine, has been patented as an antitumoral compound that decreases YAP nuclear localization by activating its phosphorylation, which subsequently reduces the expression of its target genes [ 189 ]. Interestingly, dichloroacetate promotes the nuclear-cytoplasmic translocation of YAP, but not TAZ, which is essential for DCA-mediated effects on hepatocellular carcinoma cell stemness [ 190 ]. Among the small molecule inhibitors and drugs that target the YAP protein, norcantharidin (NCTD), a derivative of cantharidin, seems to specifically target the YAP signaling pathway, modulating the subcellular distribution of YAP between the nucleus and cytoplasm; however, these data have been retracted from the publication due to lack of overall confidence [ 191 ].…”