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HMGA1 Stimulates MYH9-Dependent Ubiquitination of GSK-3β via Pi3K/Akt/C-Jun Pathway to Promote Malignant Progression and Chemoresistance in Gliomas

Background: Myosin heavy chain 9 (MYH9) plays essential role in human diseases including multiple cancers, however, little is known about the mechanism of MYH9 in gliomas. 
 
Methods: The expression of mRNA and protein was detected by clinical samples. The role of HMGA1 and MYH9 on gliomas was identified by cell functional and chemo sensitivity assay. Transcriptional regulation was confirmed by dual luciferase reporter and chromatin immunoprecipitation. Coimmunoprecipitation assay was used to verify the protein interaction and the ubiquitination. 
 
Findings: HMGA1 and MYH9 were upregulated in gliomas and correlated with WHO grade, and HMGA1 could promote malignant phenotypes and chemo resistance of glioma cells by regulating the expression of MYH9 through c-Jun-mediated transcription. Moreover, MYH9 interacted with GSK-3β and inhibited the expression of GSK-3β protein by promoting its ubiquitination, and downregulated GSK-3β could subsequently promote the nuclear translocation of β-catenin which could enhance the growth, invasion and migration, as well as temozolomide-resistance in glioma cells. Further survival analysis suggested that HMGA1 and MYH9 expression significantly correlated with patient’s survival and could be considered as independent prognostic factors in gliomas. 
 
Interpretation: Our findings provide new insights into the role of HMGA1 and MYH9 in the development of gliomas and implicate the potential application of HMGA1 and MYH9 in cancer therapy in the future. 
 
Funding: This study was supported by the National Natural Science Foundation of China, the Natural Science Foundation of Guangdong Province and the President Fund of Nanfang Hospital. 
 
Declaration of Interest: None to declare. 
 
Ethical Approval: This study obtained approval from the Ethics Committees of Nanfang Hospital for Nationalities were obtained.