Thyroid hormone suppresses hepatocarcinogenesis via DAPK2 and SQSTM1-dependent selective autophagy
Open Access
- 14 October 2016
- journal article
- research article
- Published by Taylor & Francis Ltd in Autophagy
- Vol. 12 (12), 2271-2285
- https://doi.org/10.1080/15548627.2016.1230583
Abstract
Recent studies have demonstrated a critical association between disruption of cellular thyroid hormone (TH) signaling and the incidence of hepatocellular carcinoma (HCC), but the underlying mechanisms remain largely elusive. Here, we showed that disruption of TH production results in a marked increase in progression of diethylnitrosamine (DEN)-induced HCC in a murine model, and conversely, TH administration suppresses the carcinogenic process via activation of autophagy. Inhibition of autophagy via treatment with chloroquine (CQ) or knockdown of ATG7 (autophagy-related 7) via adeno-associated virus (AAV) vectors, suppressed the protective effects of TH against DEN-induced hepatic damage and development of HCC. The involvement of autophagy in TH-mediated protection was further supported by data showing transcriptional activation of DAPK2 (death-associated protein kinase 2; a serine/threonine protein kinase), which enhanced the phosphorylation of SQSTM1/p62 (sequestosome 1) to promote selective autophagic clearance of protein aggregates. Ectopic expression of DAPK2 further attenuated DEN-induced hepatoxicity and DNA damage though enhanced autophagy, whereas, knockdown of DAPK2 displayed the opposite effect. The pathological significance of the TH-mediated hepatoprotective effect by DAPK2 was confirmed by the concomitant decrease in the expression of THRs and DAPK2 in matched HCC tumor tissues. Taken together, these findings indicate that TH promotes selective autophagy via induction of DAPK2-SQSTM1 cascade, which in turn protects hepatocytes from DEN-induced hepatotoxicity or carcinogenesis.Keywords
This publication has 37 references indexed in Scilit:
- Thyroid hormone stimulates hepatic lipid catabolism via activation of autophagyJCI Insight, 2012
- Autophagy and cancer cell metabolismSeminars in Cell & Developmental Biology, 2012
- Thyroid hormone receptors promote metastasis of human hepatoma cells via regulation of TRAILCell Death & Differentiation, 2012
- Autophagy-deficient mice develop multiple liver tumorsGenes & Development, 2011
- A Unique Metastasis Gene Signature Enables Prediction of Tumor Relapse in Early-Stage Hepatocellular Carcinoma PatientsMaterials, 2010
- Thyroid hormone receptor mutants implicated in human hepatocellular carcinoma display an altered target gene repertoireOncogene, 2009
- Thyroid Hormone Receptor β1 Acts as a Potent Suppressor of Tumor Invasiveness and MetastasisCancer Research, 2009
- Association between hypothyroidism and hepatocellular carcinoma: A case-control study in the United StatesHepatology, 2008
- The role of autophagy during the early neonatal starvation periodNature, 2004
- Thyroid hormone receptors/THR genes in human cancerCancer Letters, 2003