Oncogene-dependent addiction to carbohydrate-responsive element binding protein in hepatocellular carcinoma

Abstract

Metabolic reprogramming is a hallmark of many cancer types, including hepatocellular carcinoma (HCC). Identifying the critical players in this process might be crucial for the generation of novel and effective anti-neoplastic therapies. In the present investigation, we determined the importance of carbohydrate responsive element binding protein (ChREBP), a central player in the regulation of lipid and glucose metabolism in the liver, on the development of HCC in in vitro and in vivo models. We found that genetic deletion of ChREBP (that will be referred to as ChREBPKO mice) strongly delays or impairs hepatocarcinogenesis driven by AKT or AKT/c-Met overexpression in mice, respectively. In contrast, HCC development was found to be completely unaffected by ChREBP depletion in mice co-expressing AKT and N-Ras protooncogenes. In mouse and human HCC cell lines, suppression of ChREBP via specific small interfering RNAs (siRNAs) resulted in decreased proliferation and induction of apoptosis. Of note, these cellular events were strongly augmented by concomitant inhibition of the mitogen-activated protein kinase (MAPK) pathway. The present data indicate that ChREBP activity might be required or dispensable for HCC growth, depending on the oncogenes involved. In particular, the activation of Ras/MAPK signaling might represent a possible mechanism of resistance to ChREBP depletion in this tumor type. Additional studies are needed to unravel the molecular mechanisms rendering HCC cells insensitive to ChREBP suppression.

Carbohydrate response element binding protein (ChREBP) correlates with colon cancer progression and contributes to cell proliferation

“…It is reported that ChREBP is needed to support maximal growth of hepatoblastoma induced by a mutant form of b-catenin 37 . Recently, it has been reported that ChREBP deletion strongly delayed or impaired hepatocarcinogenesis driven by AKT or AKT/c-Met overexpression in mice, further supporting a crucial role of ChREBP in tumorigenesis 38 . However, in the same report, the authors found that ChRBEP deletion had no impact on HCC development driven by co-expression of AKT and N-Ras protooncogenes 38 .…”

“…Recently, it has been reported that ChREBP deletion strongly delayed or impaired hepatocarcinogenesis driven by AKT or AKT/c-Met overexpression in mice, further supporting a crucial role of ChREBP in tumorigenesis 38 . However, in the same report, the authors found that ChRBEP deletion had no impact on HCC development driven by co-expression of AKT and N-Ras protooncogenes 38 . Moreover, ChREBP down-regulation was found to play an essential role in mediating the transformation of epithelial to mesenchymal cells during non-small-cell lung carcinoma metastasis 39 .…”

Design, synthesis, and anticancer evaluation of novel quinoline derivatives of ursolic acid with hydrazide, oxadiazole, and thiadiazole moieties as potent MEK inhibitors

“…The latter results in changes to transcription and ultimately promotes many cellular processes including proliferation, differentiation, survival, and angiogenesis 6–8 . The dysregulation of MAPK pathway is strongly associated with many human cancers, such as hepatocellular carcinoma (HCC) 9 , non-small cell lung cancer (NSCLC) 10 , cervical carcinoma 11 , prostate carcinoma 12 , and melanoma 13 . Therefore, the signalling pathway offers attractive targets for the development of anticancer agents.…”

Clinical Value and Potential Mechanisms Exploration of GOLGA8B in Hepatocellular Carcinoma: A Comprehensive Investigation Based on Real-Time Quantitative Polymerase Chain Reaction, RNA-seq, Microarray and Immunohistochemistry

“…As reported, in 50-100% of HCC cases, the MAPK pathway is activated and is related to poor prognosis [38]. Carbohydrate-responsive element-binding protein, which acts an important role in lipid and glucose metabolism in liver, takes effect in the development of HCC by regulating the MAPK pathway [39].…”