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HACE1 Is a Potential Tumor Suppressor in Osteosarcoma Amal M El-Naggar1,2,3,Paulw.Clarkson4,Gianlucanegri1,2, Busra Turgu1,2, Fan Zhang5, Michael S

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HACE1 Is a Potential Tumor Suppressor in Osteosarcoma Amal M El-Naggar1,2,3,Paulw.Clarkson4,Gianlucanegri1,2, Busra Turgu1,2, Fan Zhang5, Michael S El-Naggar et al. Cell Death and Disease (2019) 10:21 https://doi.org/10.1038/s41419-018-1276-4 Cell Death & Disease ARTICLE Open Access HACE1 is a potential tumor suppressor in osteosarcoma Amal M El-Naggar1,2,3,PaulW.Clarkson4,GianLucaNegri1,2, Busra Turgu1,2, Fan Zhang5, Michael S. Anglesio1,6 and Poul H. Sorensen1,2 Abstract Osteosarcoma is a malignant bone sarcoma characterized by extensive genomic disruption and a propensity for metastatic spread. Osteoid production suggests a close relationship with normal osteoblasts, and the latter are the presumptive cell of origin of this disease. The HACE1 gene, localized to human chromosome 6q21, encodes the HACE1 HECT E3 ligase, a tumor suppressor in diverse tumors that acts in part by targeting the activated form of RAC1 GTPase for proteasomal degradation. Disruption or loss of 6q21 is relatively common in osteosarcomas, and Hace1−/−/Tp53 +/− mice frequently develop osteosarcomas, in contrast to Tp53+/− mice, which do not. This suggests an unexplored link between HACE1 loss and osteosarcoma. Here we compared HACE1 expression in normal osteoblasts and osteosarcoma cell lines in vitro by western blotting and quantitative RT-PCR, and in human osteosarcoma specimens by immunohistochemistry. Both HACE1 transcript and protein levels were reduced in osteosarcoma compared to osteoblasts in vitro. Reduced HACE1 expression in osteosarcoma tumors was observed in 76% of cases and associated with high-grade lesions. Further, clonally derived pairs of high and low metastatic osteosarcoma cell lines showed significant downregulation in the high compared to corresponding low metastatic cells. Ectopic expression of HACE1 markedly inhibited anchorage-independent growth and cell motility of HACE1 osteosarcoma cell lines, and was associated with reduced RAC1 activation and decreased reactive oxygen species (ROS). Finally, HACE1 1234567890():,; 1234567890():,; 1234567890():,; 1234567890():,; overexpression blocked osteosarcoma xenograft growth and dramatically reduced pulmonary metastases. These findings point to a potential tumor suppressor function for HACE1 in osteosarcoma. Introduction later life, with 30% of patients being over 40 years of age4. Osteosarcoma is a malignant bone tumor commonly Several sub-types of osteosarcoma are described, which arising in areas of rapid bone growth, such as the distal have in common the production of osteoid by malignant – femur and proximal tibia1 3. It represents the most cells, and a propensity for metastatic spread, particularly common bone sarcoma, comprising approximately 20% of to lungs2,5. all bone tumors and about 5% of pediatric tumors1.Itis Most cases of osteosarcoma are sporadic, but certain predominantly a disease of adolescence and young environmental and hereditary factors have been asso- adulthood, with 60% of patients aged under 25 years at ciated with elevated risk osteosarcoma6,7. The former diagnosis; however, there is a second peak of incidence in include exposure to ionizing radiation and Paget disease, with dysregulated bone recycling, both of which well- recognized risk factors for the development of secondary Correspondence: Poul H. Sorensen ([email protected]) osteosarcoma8,9. Hereditary conditions associated with 1Department of Pathology and Laboratory Medicine, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada osteosarcoma include familial retinoblastoma, 2Department of Molecular Oncology, British Columbia Cancer Research Centre, Li–Fraumeni syndrome, and Rothmund–Thomson syn- Vancouver, BC, Canada drome10. The tumor suppressor gene TP53 is the most Full list of author information is available at the end of the article. 6 These authors contributed equally: Amal M. El-Naggar, Paul W. Clarkson well-characterized gene implicated in osteosarcoma . Loss Edited by M Daugaard © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a linktotheCreativeCommons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Official journal of the Cell Death Differentiation Association El-Naggar et al. Cell Death and Disease (2019) 10:21 Page 2 of 16 of p53 due to somatic mutation, or germline inactivation the RAC1 GTPase for ubiquitylation and subsequent as in the autosomal dominant disorder Li–Fraumeni proteosomal degradation32,33. By targeting RAC1 at – syndrome, predisposes to osteosarcoma11 13. TP53 is membrane-associated RAC1-dependent NADPH oxidase commonly inactivated in osteosarcoma either by allelic complexes, HACE1 reduces ROS levels in vitro and loss, point mutations, or gene rearrangements12,14,15. in vivo by blocking NADPH oxidase-mediated superoxide Up to 26.5% of non-hereditary osteosarcoma cases generation34. Recently, it was shown that HACE1 is show somatic loss of p5316, and 30% of Li–Fraumeni phosphorylated at serine 385 by PAK1 kinase, resulting in syndrome patients develop osteosarcoma17. TP53 muta- lower efficiency of RAC1 ubiquitination35. Further, tions are associated with unfavorable outcome18, HACE1 has been shown to play critical roles in and up to 60% of high-grade osteosarcomas show TNFR1 signaling36. HACE1 is also reported to ubiquity- TP53 mutations, compared with 1% of low-grade late the autophagy receptor Optineurin (OPTN), which in osteosarcoma11,19,20. turn facilitates OPTN interactions with p62/SQSTM1 to Another well-characterized gene implicated in osteo- activate autophagy to inhibit growth and tumorigenicity sarcoma is RB1, localized to chromosome 13q14 and of lung cancer cells37. HACE1 also provides cytoprotec- encoding the 110 kDa pRB1 protein that negatively reg- tive regulation of proteotoxic stress responses, such as in ulates cell cycle progression21. Loss of RB in osteosarcoma cardiac cells38. Moreover HACE1, via interactions with is associated with poor patient outcome22,23. Other Rab proteins, is targeted to Golgi membranes, regulating genetic abnormalities are also associated with increased Golgi biogenesis, Golgi traffic, and postmitotic Golgi risk of osteosarcoma, such as mutations of RecQ heli- membrane fusion39. cases, germline RECQL4 inactivation resulting in HACE1 expression is reduced in many tumor types Rothmund–Thomson syndrome24, BLM(RECQL3) inac- compared to corresponding normal tissues, including tivation resulting in Bloom syndrome, or WRN inactiva- Wilms’ tumor30,31, breast carcinoma40, lung adenocarci- tion resulting in Werner syndrome11,25. MicroRNA and noma, angiosarcoma, and lymphoma31. Moreover, loss of copy number variation (CNV) analyses have further heterozygosity at chromosome 6q21 is described in mul- identified hsa-miR-27a-3p, hsa-miR-9-5p, hsa-miR-182- tiple cancers31, including ovarian carcinoma, non-Hodg- 5p, FRS2, CORO1C, FOXP1, and CPEB4 as potentially kin’s lymphoma, pancreatic carcinoma, prostate contributing to the pathogenesis of osteosarcoma26. carcinoma, and osteosarcoma31,41. Previously, we repor- Moreover, next-generation sequencing of patients with ted that Hace1−/− mice develop late onset tumors across conventional high-grade osteosarcoma identified 15 genes all three germ layers, including osteosarcomas31. More- with variations only in the treatment non-responder over, crossing Hace1−/− mice into a Tp53+/− back- patients, including ERBB4, Thrombospondin I (THBS1), ground led to an increased rate of osteosarcoma DIS3, and BCLAF27. Whole-genome sequencing of 20 compared to Hace1−/− mice, while osteosarcomas were osteosarcomas and matched normal tissue showed mul- not observed in Hace1+/+/Tp53+/− mice31. This sug- tiple tumor-associated structural variations and copy gests that HACE1 loss is associated with osteosarcoma number alterations as well as kataegis (single-nucleotide development. However, studies directly addressing the variations with localized hypermutation)28. Of note, p53 link between HACE1 and osteosarcoma are currently pathway mutations were identified in all tumor samples. lacking. Somatic alterations affecting RB1, ATRX, and DLG2 genes were detected in 29–53% of the tumors. Recently, exome Results sequencing of 31 osteosarcomas showed that over 80% HACE1 expression is reduced in osteosarcoma cells exhibited mutational signatures characteristic of BRCA1/2 compared to normal osteoblasts deficiency29, further highlighting the role of altered DNA To investigate potential links between HACE1 and damage repair pathways in osteosarcoma. osteosarcoma, we first analyzed publicly available data- HACE1 (HECT domain and ankyrin-repeat-containing bases for HACE1 mRNA expression in osteosarcoma E3 ubiquitin-protein ligase 1) was originally cloned from samples (GSE33382) compared to mesenchymal stem chromosome 6q21 translocation breakpoints in pediatric cells (MSCs) (GSE28974). HACE1 expression was sig- Wilms’ tumor30. HACE1 is a HECT family E3 ligase with nificantly lower in osteosarcoma samples compared to an N-terminal ankyrin-repeat
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