Transcriptome profiling of caspase-2 deficient EμMyc and Th-MYCN mouse tumors identifies distinct putative roles for caspase-2 in neuronal differentiation and immune signaling

Abstract

Caspase-2 is a highly conserved cysteine protease with roles in apoptosis and tumor suppression. Our recent findings have also demonstrated that the tumor suppression function of caspase-2 is context specific. In particular, while caspase-2 deficiency augments lymphoma development in the EμMyc mouse model, it leads to delayed neuroblastoma development in Th-MYCN mice. However, it is unclear how caspase-2 mediates these differential outcomes. Here we utilized RNA sequencing to define the transcriptomic changes caused by caspase-2 (Casp2−/−) deficiency in tumors from EμMyc and Th-MYCN mice. We describe key changes in both lymphoma and neuroblastoma-associated genes and identified differential expression of the EGF-like domain-containing gene, Megf6, in the two tumor types that may contribute to tumor outcome following loss of Casp2. We identified a panel of genes with altered expression in Th-MYCN/Casp2−/− tumors that are strongly associated with neuroblastoma outcome, with roles in melanogenesis, Wnt and Hippo pathway signaling, that also contribute to neuronal differentiation. In contrast, we found that key changes in gene expression in the EμMyc/Casp2−/− tumors, are associated with increased immune signaling and T-cell infiltration previously associated with more aggressive lymphoma progression. In addition, Rap1 signaling pathway was uniquely enriched in Casp2 deficient EμMyc tumors. Our findings suggest that Casp2 deficiency augments immune signaling pathways that may be in turn, enhance lymphomagenesis. Overall, our study has identified new genes and pathways that contribute to the caspase-2 tumor suppressor function and highlight distinct roles for caspase-2 in different tissues.

Caspase-2 protects against ferroptotic cell death

“…The RNA-sequencing data identified differential expression of oxidative stress-related genes including SESN2, HMOX1, SLC7A11 in mut-p53 cancer cells without caspase-2 under basal conditions. These observations are consistent with previous studies implicating the association of caspase-2 loss with transcriptional regulation of genes involved in tumorigenesis and redox signaling [ 4 , 14 ]. Collectively, these studies imply that caspase-2 loss supports a favorable environment for ferroptosis and does not simply act by enhancing the kinetics of erastin effect.…”

“…Caspase-2 has previously been shown to influence transcriptome changes driven by oncogene activation and tumor suppressor loss in a context-specific manner [ 4 ]. To identify the transcriptomic differences and gene enrichment pathways affected by CASP2 deficiency in mut-p53 cancer cells, we carried out RNA sequencing in H1299p53 R273H cancer cells with acute loss and knockout of caspase-2 (Fig.…”

Caspase-2 protects against ferroptotic cell death

“…The RNA sequencing data identified differential expression of oxidative stress related genes including SESN2, HMOX1, SLC7A11 in mut-p53 cancer cells without caspase-2 under basal conditions. These observations are consistent with previous studies implicating association of caspase-2 loss with transcriptional regulation of genes involved in tumorigenesis and redox signaling (4,14). Collectively, these studies imply that caspase-2 loss supports a favourable environment for ferroptosis and does not simply act by enhancing kinetics of erastin effect.…”

“…Caspase-2 is the most conserved member of the caspase family and is well studied for its role as a tumor suppressor under conditions of oncogenic or replicative stress. Previous in vivo studies have established that caspase-2 deficient (Casp2 −/− ) mice do not develop spontaneous tumors (1) but have enhanced susceptibility to tumorigenesis promoted by activation of oncogenes (K-Ras, EμMyc and MMTV/c-neu) (2)(3)(4)(5) or loss of a critical tumor suppressor gene (ATM) (6). Furthermore, studies from human cancers have reported that the CASP2 gene located on Ch7q is frequently deleted in haematological malignancies (7).…”

The p53-caspase-2 axis in the cell cycle and DNA damage response

“…Notably, this correlation was observed in neuroblastoma patients with nonamplified MYCN 96 . The tissue- and context-specific tumor suppressor function of caspase-2 was also apparent in the distinct transcription profiles of caspase-2-deficient Eμ-Myc and TH -MYCN mouse tumors 97 .…”