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CIC Protein Instability Contributes to Tumorigenesis in Glioblastoma

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CIC Protein Instability Contributes to Tumorigenesis in Glioblastoma ARTICLE https://doi.org/10.1038/s41467-018-08087-9 OPEN CIC protein instability contributes to tumorigenesis in glioblastoma Severa Bunda1, Pardeep Heir1, Julie Metcalf1, Annie Si Cong Li 1, Sameer Agnihotri1,7, Stefan Pusch 5,6, Mamatjan Yasin1, Mira Li 1, Kelly Burrell1, Sheila Mansouri1, Olivia Singh 1, Mark Wilson1, Amir Alamsahebpour1, Romina Nejad1, Bethany Choi 1, David Kim1, Andreas von Deimling5,6, Gelareh Zadeh1,2,3 & Kenneth Aldape1,4 1234567890():,; Capicua (CIC) is a transcriptional repressor that counteracts activation of genes downstream of receptor tyrosine kinase (RTK)/Ras/ERK signaling. It is well-established that tumorigen- esis, especially in glioblastoma (GBM), is attributed to hyperactive RTK/Ras/ERK signaling. While CIC is mutated in other tumors, here we show that CIC has a tumor suppressive function in GBM through an alternative mechanism. We find that CIC protein levels are negligible in GBM due to continuous proteasome-mediated degradation, which is mediated by the E3 ligase PJA1 and show that this occurs through binding of CIC to its DNA target and phosphorylation on residue S173. PJA1 knockdown increased CIC stability and extended survival using in-vivo models of GBM. Deletion of the ERK binding site resulted in stabilization of CIC and increased therapeutic efficacy of ERK inhibition in GBM models. Our results provide a rationale to target CIC degradation in Ras/ERK-driven tumors, including GBM, to increase efficacy of ERK inhibitors. 1 MacFeeters Hamilton Centre for Neuro-Oncology Research, Princess Margaret Cancer Centre, Toronto, ON M5G 2C1, Canada. 2 Division of Neurosurgery, Toronto Western Hospital, Toronto, ON M5G 2C1, Canada. 3 Insititute of Medical Science, University Health Network and University of Toronto, Toronto, ON M5S 3E1, Canada. 4 Laboratory of Pathology, National Cancer Institute, Bethesda, MD 20892, USA. 5 Department of Neuropathology, Institute of Pathology, Heidelberg University Hospital, Heidelberg D-69120, Germany. 6 German Consortium of Translational Cancer Research (DKTK), Clinical Cooperation Unit Neuropathology German Cancer Research Center (DKFZ), Heidelberg, D-69120 Germany. 7Present address: Department of Neurosurgery, University of Pittsburgh Medical Center, UPMC Presbyterian, Suite B-400, 200 Lothrop Street, Pittsburgh, PA 15213, USA. Correspondence and requests for materials should be addressed to G.Z. (email: [email protected]) or to K.A. (email: [email protected]) NATURE COMMUNICATIONS | (2019) 10:661 | https://doi.org/10.1038/s41467-018-08087-9 | www.nature.com/naturecommunications 1 ARTICLE NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-018-08087-9 lioblastoma (GBM) is the most common and malignant ERK signaling regulates CIC to alleviate target gene repression. In Gprimary neuroepithelial tumor and remains incurable particular, it is not established whether CIC is as an important despite aggressive therapy. Molecular alterations of var- signaling regulator in GBM. The ETS family of oncogenic tran- ious signaling pathways potentiate receptor tyrosine kinase (RTK) scription factors, ETV1, ETV4, and ETV5 downstream of RTK/ activation, such as the frequent EGFR amplifications or variant III Ras/ERK activation have been shown to mediate gliomagen- mutations (EGFRvIII) that are linked with the aggressive behavior esis14,25, yet the role of CIC, a well-established repressor of these of GBMs1–3. Unfortunately, results from clinical trials targeting genes21, is unknown. To explore this, we first examined the Ras/Raf/MEK/ERK signaling downstream of RTK have only had expression of CIC protein in human newly diagnosed GBM limited success4, indicating a need for increasing understanding human tumors. Interestingly, in 30/30 GBM patient tumor of the mechanisms regulating this pathway in GBM. samples, CIC protein level was substantially reduced or absent The high-mobility group (HMG)-box transcriptional repressor compared to lysates derived from non-neoplastic brain tissue capicua (CIC) has recently emerged as a conserved nuclear sensor (Figure 1a and Supplementary Figure 1A and C). By contrast, CIC of RTK signaling in Drosophila and mammals5. In unstimulated mRNA expression was readily detected in these samples, at levels cells, CIC represses EGFR/Ras pathway-responsive genes. Fol- equal to or exceeding that of normal brain (Fig. 1b and Supple- lowing EGFR stimulation, CIC repression is relieved, allowing for mentary Figure 1B and D). Further investigation of the nuclear the expression of target genes. The best-characterized CIC targets fraction and confirmed that CIC was localized to the nuclear in mammalian cells are the oncogenic transcription factors ETV1, fraction in normal brain, but was indeed absent nuclear fractions ETV4, and ETV55, which mediate cell proliferation, motility and of GBM tumors (Figure 1c). Extending this to lower-grade glio- invasion downstream of Ras6. Much has been learned from studies mas, CIC protein expression was detected at much higher levels in Drosophila, where CIC was first described to be involved in in the majority of lower-grade astrocytoma samples studied developmental patterning and cell fate modulated through EGFR (Fig. 1d). The loss of CIC protein in patient-derived samples activation7–10, in a manner termed ‘default repression’. While correlated with de-repression the CIC targets, ETV1 and ETV5, CIC’s function is less well-understood in vertebrate organisms, the in human GBM (Figure 1a and Supplementary Figure 1C) and in importance of CIC protein in maintaining cellular homeostasis lower-grade astrocytoma (Fig. 1d). In addition to these experi- downstream of EGFR/Ras/ERK signaling has recently become mental findings, we mined Cancer Genome Atlas (TCGA) data, evident in humans11–13, but the molecular mechanisms governing to show that ETV1, ETV5, and ETV4 mRNA levels were higher CIC functions in normal cells and in cancer are lacking. in human GBM samples relative to normal brain (Supplementary Investigation into the molecular function of CIC in cancer and Figure 1F). GBM in particular, is further merited by recent findings con- Extending this to in vitro model systems, we found, similar to necting CIC’s downstream target ETV1 in GBM14. patient-GBM tumor samples, that CIC protein levels were CIC is not mutated in GBM, but mutations of this gene, located reduced in human-derived established GBM cell lines, despite on chromosome 19q, occur in 70% of 1p19q-co-deleted oligoden- abundant CIC mRNA levels (Fig. 1e, f). CIC level was also drogliomas15–18. Decreased CIC expression is correlated with negligible in a well-established mouse glioma 261 (GL261) cell poorer outcome in these tumors19. Two CIC isoforms exist that line that harbors mutations in the K-Ras and p53 genes, differ in size, the short (CIC-S) and the long (CIC-L), and in their frequently used for GBM therapy26, compared to normal mouse N-terminal region20. Given that the disease-associated mutations astrocytes (Figure 1g). Consistently, GBM cell lines also showed map to the CIC-S isoform of the protein, which suggests that the elevated ETV1, ETV5, and ETV4 expression compared to CIC-S isoform may be more important in tumorigenesis, we focus normal human astrocytes (NHA) (Figure 1g, Supplementary on the CIC-S isoform in the current study referred to as CIC Figure 1G and H). Likewise, loss of CIC protein and elevated throughout the manuscript21. In addition to loss-of-function ETV levels were also seen in six different patient-derived glioma mutations in oligodendrogliomas, and other tumor types, translo- stem cells (GSC) compared to normal human stem cells (NSC) cation events resulting in gene fusions of CIC with either DUX4 or (Figure 1h, i). FOXO4 has been shown in round cell sarcomas22,23. Additionally, To establish in vivo relevance, we generated intracranial CIC has most recently been shown to suppress invasion and xenografts of GBMs using murine glioma GL261 cells, GSC metastasis in lung cancer, through an effector identified as model and an established cell line (GSC 8-18 and U87). All three MMP2412. In addition, germline CIC inactivation in adult mice was models revealed that CIC protein remained low and were shown to induce T-cell acute lymphoblastic lymphoma24.Despite substantially reduced in intracranial xenografts compared to clear genetic evidence of its connection to one of the most normal contralateral brain parenchyma. Consistently, the levels of important pathways in cancer, molecular mechanisms governing phosphorylated ERK (pERK), ETV1, and ETV5 were high in CIC regulation by Ras/ERK signaling and its potential involvement tumors compared to normal unaffected brain (Fig. 1j–l and in GBM remain unknown. Supplementary Figure 1I). Additionally, we investigated CIC in In this study, we present data to establish a role for CIC in Ras-driven transgenic mouse model of GBM, (RasB8)27. High- GBM. We find that activation of Ras/ERK signaling mediates grade tumors from RasB8 mice were isolated and compared to ubiquitylation and degradation of CIC by a nuclear E3 ligase wild-type control mice. In agreement with our xenograft model, PRAJA1 (PJA1) to drive GBM growth. We provide mechanistic RasB8 tumors displayed CIC protein loss and a concomitant insights into regulation of CIC downstream of EGFR activation via increase in ETV1 and ETV5 (Figure 1m). Taken together, these serine/threonine phosphorylation. Importantly, a degradation- results indicate that CIC is strikingly reduced or absent at the resistant CIC mutant, insensitive to the effects of ERK stimulation,
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