Abstract
Hepatitis B virus (HBV) is causally linked to hepatocellular injury and cell death, which are followed by hepatocellular carcinoma (HCC) after a long latent period. The HBV derived X protein (HBX) is the most potent carcinogenic factor for HCC, however, the molecular mechanism of HBX-induced transformation of hepatic cells in HCC is poorly understood. We have shown that nuclear receptor co-repressor (NCoR) is essential for the spatial repression of global transcription by the promyelocytic leukemia oncogenic domains (PODs), a frequent target of viral oncoproteins like HBX and that disintegration of PODs due to misfolded conformation dependent loss (MCDL) of NCoR is linked to promyelocytic and monocytic acute myeloid leukemia (AML). Given the key role of NCoR in cellular homeostasis across various tissue subtypes, we hypothesized that HBX-induced MCDL of NCoR might be linked to HCC through similar mechanism. Based on this hypothesis, the conformation of NCoR in HCC derived tumor cells and primary human tissue sections were analyzed and a selective MCDL of NCoR in HBX positive HCC cells was identified. HBX triggered the misfolding of NCoR through ubiquitination, followed by its degradation by autophagy, thus suggesting a cross talk between ubiquitin proteasome system (UPS) and autophagy lysosomal pathway (ALP) in MCDL of NCoR in HBX positive HCC cells. SiRNA-induced NCoR ablation selectively impaired the growth and survival of HBX positive HCC cells, suggesting a role of MCDL in the growth and survival of HBX positive HCC cells. These finding identify a possible crosstalk between UPS and ALP in the misfolding and loss of NCoR in HBX positive HCC cells and suggest a role of autophagic recycling of misfolded NCoR in the activation of oncogenic metabolic signaling in HCC. The misfolded NCoR reported in this study represents a novel conformation based molecular target which could be valuable in the design and development of tumor cell specific diagnostic and therapeutic approach for HBX positive HCC.
Highlights
Primary liver cancer is one of the most lethal human malignancies for which no effective treatment is available
We have previously shown that PML-RAR, the fusion oncoprotein linked to the pathogenesis of promyelocytic acute myeloid leukemia (AML), can induce a characteristic ubiquitin-proteasome system (UPS) mediated misfolding of nuclear receptor co-repressor (NCoR) protein, which contributed to the disintegration of PML oncogenic domains (PODs) in promyelocytic AML [15, 16]
The faint intact NCoR band observed in HBV X (HBX) positive hepatocellular carcinoma (HCC) cells SKHep1 and Snu449 appeared to be slightly higher in molecular weight when compared to NCoR of HepG2 cells, the HBX negative HCC cells; suggesting that NCoR found in HBX positive HCC cells might have undergone some sort of post-translational modification (Figure 1A)
Summary
Primary liver cancer is one of the most lethal human malignancies for which no effective treatment is available. A potent inducer of differentiation of promyelocytic AML cells, abrogated NCoR misfolding and reorganized the PODs in promyelocytic AML cells, suggesting an important role of PODs in cellular defense against malignant transformation [17] These finding suggested an important role of NCoR in the structural and functional integrity of PODs, which oncogenic virus like HBV must overcome to promote cellular transformation. Given the nearly identical effect of PML-RAR and pathogenic viral proteins on the structural and functional integrity of PODs, we hypothesized the HBX-induced transformation of liver cells might be the consequence of a prosurvival mechanism selectively activated by misfolded NCoR protein in HBX positives HCC cells. We report that HBX promotes misfolding of NCoR protein through UPS and that degradation of misfolded NCoR through autophagy lysosomal pathway (ALP) is linked to the growth and survival of tumor cells in HBX positive HCC cells
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