EHD1 promotes the cancer stem cell (CSC)‐like traits of glioma cells via interacting with CD44 and suppressing CD44 degradation

Abstract

Plenty of evidence has shown that endocytosis plays a key role in cancer progression; however, its effects in the progression of cancer stem cells (CSCs) are still fragmentary. In the present study, we firstly identified that mammalian Eps15 homology domain protein 1 (EHD1), an endocytic and metastasis‐associated gene, was upregulated in the 3D non‐adherent spheres derived from glioma cells compared to that in the corresponding parental cells. Further functional experiments revealed that EHD1 knockdown reduced the CSC‐like traits of glioma cells, which were evident by the decrease of sphere‐formation ability, ALDH1 activity, and CSC markers' expression. Additionally, EHD1 knockdown attenuated the tumor‐initiating ability of glioma cells in vivo. Furthermore, it was shown that EHD1 bound to CD44, enhanced CD44 stability, and prevented its total ubiquitination. Indeed, overexpression of CD44 rescued the inhibitory effects of EHD1 knockdown on the CSC‐like traits of glioma cells. Finally, through the online dataset analysis, we found that EHD1 indeed exhibited a higher level in glioma tissues relative to that in normal tissues, and a positive correlation with CSC markers' expression in glioma tissues. Notably, EHD1 expression was negatively correlated with the overall survival and relapse‐free survival of glioma patients. Thus, this work indicates that EHD1 might be a potent target for glioma progression, especially through breaking the EHD1–CD44 interaction.

EHD1-dependent traffic of IGF-1 receptor to the cell surface is essential for Ewing sarcoma tumorigenesis and metastasis

“…These cell biological findings raise the possibility that overexpression of EHD1 in tumors could promote RTK-dependent oncogenic signaling by enabling the cell surface display of RTKs on tumor cells. This idea is consistent with recent findings in which EHD1 overexpression has been observed in various cancers, often correlating with shorter survival, and cell-based studies using gene knockdown or overexpression strategies that support the role of EHD1 overexpression to promote tumorigenesis, chemotherapy resistance, epithelial-mesenchymal transition, stem cell behavior and glycolysis in various tumor models 6–15 . These studies have linked EHD1 overexpression to distal signaling alterations such as the activation of NFκB, β-catenin/c-Myc pathways that are not immediately linked to EHD1’s core vesicular traffic roles in endocytic recycling and Golgi to cell surface RTK traffic.…”

“…While our studies focus on the linkage of EHD1 with an RTK, EHD1 overexpression may also regulate other oncogenesis-related cell surface receptors, given its broader roles. Indeed, EHD1 overexpression was shown to promote cancer stem cell-like traits in glioblastoma and lung cancer by promoting CD44 recycling while suppressing its degradation 60, 61 , promote cisplatin resistance in NSCLC by regulating cisplatin accumulation in cells, presumably by regulating transporter levels 62 , and potentiate angiogenesis by promoting b2 adrenergic receptor recycling 63 . Cell biological studies have also shown a positive role of EHD1 in β1 integrin recycling 45 .…”

EHD1-dependent traffic of IGF-1 receptor to the cell surface is essential for Ewing sarcoma tumorigenesis and metastasis

“…These cell biological findings raise the possibility that overexpression of EHD1 in tumors could promote RTK-dependent oncogenic signaling by enabling the cell surface display of RTKs on tumor cells. This idea is consistent with recent findings of EHD1 overexpression in various cancers, often correlating with shorter survival, and the cell-based studies using gene knockdown or overexpression strategies that support the role of EHD1 overexpression to promote tumorigenesis, chemotherapy resistance, epithelial-mesenchymal transition, stem cell behavior, and glycolysis in various tumor models [6][7][8][9][10][11][12][13][14][15] . These studies have linked EHD1 overexpression to distal signaling alterations such as the activation of NFkB, β-catenin, and c-Myc pathways that are not immediately linked to EHD1's core vesicular traffic roles in endocytic recycling and Golgi to cell surface RTK traffic.…”

“…Our studies demonstrating a requirement of EHD1 for IGF-1R cell surface traffic and signaling as a key component for its requirement for tumorigenic and metastatic behaviors of EWS cell models raise the question of whether EHD1 might be a suitable target in EWS since the impact of IGF-1R targeting has been low to modest 31,34,37,44 . Given the EHD1 regulation of IGF-1R and other RTKs 4,5 as well as its targeting of additional pathways shown in other cancers 9,11,12,[14][15][16]70 , it appears likely that EHD1 targeting may still be viable and may potentially be combined with IGF-1R targeting. Additionally, the cell surface levels of RTKs not only dictate the levels of ligand-induced and kinase-dependent signaling as documented for IGF-1R in this study, but also dictate their kinase-independent signaling as demonstrated for several RTKs including EGFR and IGF-1R [71][72][73][74][75][76] .…”

“…While our studies focus on the linkage of EHD1 with an RTK, EHD1 overexpression may also regulate other oncogenesisrelated cell surface receptors, given its broader roles. Indeed, EHD1 overexpression was shown to promote cancer stem celllike traits in glioblastoma and lung cancer by promoting CD44 recycling while suppressing its degradation 15,70 , promote cisplatin resistance in NSCLC by regulating cisplatin accumulation in cells presumably by regulating transporter levels 9 , and potentiate angiogenesis by promoting b2 adrenergic receptor recycling 13 . Cell biological studies have also shown a positive role of EHD1 in β1 integrin recycling 56 .…”