Stressing the Importance of CHOP in Liver Cancer

Hepatocellular carcinoma (HCC) is the third leading cause of cancer death and the fifth most common solid tumor worldwide [1,2]. Liver tumorigenesis is a multistep process in which external stimuli such as chronic inflammation or cirrhosis lead to the development of clonal populations of dysplastic hepatocytes that accumulate genetic changes and evolve into malignant foci [2]. Among the most common risk factors for HCC pathogenesis include viral hepatitis, alcoholism, and obesity [1,3]. The same insults that predispose to HCC are known to induce endoplasmic reticulum (ER) stress pathways. One such pathway, known as the unfolded protein response (UPR), is triggered by the accumulation of incompletely folded proteins in the ER lumen [4–6]. Stimulation of the UPR results in the activation of three transmembrane proteins that induce downstream effectors to alter gene expression and ultimately modulate ER function. One of these UPR transmembrane proteins is protein kinase RNA (PKR)-like ER kinase (PERK), which phosphorylates eIF2a, leading to a transient translational blockade. A related pathway that shares transcriptional targets with the UPR is the integrated stress response (ISR) pathway. When triggered by viral infection or amino acid starvation the ISR also initiates eIF2a-dependent signaling events [7]. Although the UPR and ISR pathways are active in distinct human tumor types and the UPR is implicated in HCC [8– 10], their relative contribution to the pathogenesis of HCC has remained uncharacterized. In this issue of PLOS Genetics, Rutkowski and colleagues (DeZwaan-McCabe et al., [11]) sought to determine whether the UPR pathway was induced in murine liver tumors that developed in a Sleeping Beauty (SB) transposon-induced insertional mutagenesis screen [12,13]. The application of transposon-based approaches to cancer gene identification provides a powerful opportunity to examine the consequences of specific mutations in the context of in vivo tumor development [14]. Whole transcriptome sequencing of liver tumors generated in an SB-mediated liver tumorigenesis screen identified an induction of C/EBP Homologous Protein (CHOP), a stress-regulated transcription factor, in multiple SB-induced tumors. Upon further analysis, components of the two PERKindependent arms of the UPR pathway were not altered at the transcript level, leading the authors to further investigate the role of the ISR and CHOP in HCC. CHOP, which has a diverse repertoire of transcriptional targets and modes of transcriptional modulation, was previously known to mediate apoptosis in response to ER stress [15–17]. Accordingly, several studies implicate CHOP as a putative tumor suppressor. In contrast to this, chromosomal translocations fusing CHOP to FUS/TLS and EWS have been identified in several cancers, hinting that CHOP may also play an oncogenic role in tumorigenesis in certain contexts [18,19].