CCAAT/enhancer binding protein α predicts poorer prognosis and prevents energy starvation–induced cell death in hepatocellular carcinoma

Abstract

CCAAT enhancer binding protein α (C/EBPα) plays an essential role in cellular differentiation, growth, and energy metabolism. Here, we investigate the correlation between C/EBPα and hepatocellular carcinoma (HCC) patient outcomes and how C/EBPα protects cells against energy starvation. Expression of C/EBPα protein was increased in the majority of HCCs examined (191 pairs) compared with adjacent nontumor liver tissues in HCC tissue microarrays. Its upregulation was correlated significantly with poorer overall patient survival in both Kaplan-Meier survival (P = 0.017) and multivariate Cox regression (P = 0.028) analyses. Stable C/EBPα-silenced cells failed to establish xenograft tumors in nude mice due to extensive necrosis, consistent with increased necrosis in human C/EBPα-deficient HCC nodules. Expression of C/EBPα protected HCC cells in vitro from glucose and glutamine starvation–induced cell death through autophagy-involved lipid catabolism. Firstly, C/EBPα promoted lipid catabolism during starvation, while inhibition of fatty acid beta-oxidation significantly sensitized cell death. Secondly, autophagy was activated in C/EBPα-expressing cells, and the inhibition of autophagy by ATG7 knockdown or chloroquine treatment attenuated lipid catabolism and subsequently sensitized cell death. Finally, we identified TMEM166 as a key player in C/EBPα-mediated autophagy induction and protection against starvation. Conclusion: The C/EBPα gene is important in that it links HCC carcinogenesis to autophagy-mediated lipid metabolism and resistance to energy starvation; its expression in HCC predicts poorer patient prognosis. (Hepatology 2015;61:965–978)

Acetyl‐coenzyme A carboxylase alpha promotion of glucose‐mediated fatty acid synthesis enhances survival of hepatocellular carcinoma in mice and patients

“…We showed that HCC cells with a high level of lipid content displayed a survival advantage against nutrient starvation. Similar to our findings, it has been reported that autophagy‐mediated lipid metabolism is linked to resistance to energy starvation in HCC carcinogenesis . Cellular stress, including nutrient deficiency, facilitated lipid droplet biosynthesis and mobilization, which was required for fueling FAO to maintain cells survival under these conditions .…”

“…Alternations of ACCα had no impact on autophagic flux, as revealed by conversion of LC3B‐II and degradation of SQSTM1 in hepatoma cells during both glucose and glutamine starvation (http://onlinelibrary.wiley.com/doi/10.1002/hep.28415/suppinfo). More important, pharmacological inhibition of autophagy with chloroquine (CQ) further increased starvation‐stimulated LC3B‐II amounts, regardless of ACCα expression levels in hepatoma cells (http://onlinelibrary.wiley.com/doi/10.1002/hep.28415/suppinfo). Thus, it seemed that ACCα regulated lipid metabolism and protected HCCs against starvation in an autophagy‐independent manner.…”

The combination of circulating long noncoding RNAs AK001058, INHBA-AS1, MIR4435-2HG, and CEBPA-AS1 fragments in plasma serve as diagnostic markers for gastric cancer

“…Expression of CEBPA protein was increased in HCCs [35], and epigenetic aberrations in regulating CEBPA expression contributed to leukemic transformation in acute myeloid leukemia[36]. INHBA mRNA and protein expression is commonly elevated in primary human NSCLC, and it promotes tumor metastasis [37].…”

Lipid Metabolism in Liver Cancer

“…However, active fatty acid oxidation in the resistant HCC cells can protect cells with necessary ATP generation even if the exogenous glucose is unavailable and the endogenous glycogen is depleted. The author recently confirmed this hypothesis by comparing the starvation-sensitive with -resistant HCC cells [81]. The results demonstrated that the sensitive HCC cells, lack of an important transcription factor C/EBPalpha, could not initiate fatty acid oxidation and died within 12 h during enforced glucose deprivation in vitro.…”