HMGA1 stimulates MYH9-dependent ubiquitination of GSK-3β via PI3K/Akt/c-Jun signaling to promote malignant progression and chemoresistance in gliomas

Abstract

Myosin heavy chain 9 (MYH9) plays an essential role in human diseases, including multiple cancers; however, little is known about its role in gliomas. In the present study, we revealed that HMGA1 and MYH9 were upregulated in gliomas and their expression correlated with WHO grade, and HMGA1 promoted the acquisition of malignant phenotypes and chemoresistance of glioma cells by regulating the expression of MYH9 through c-Jun-mediated transcription. Moreover, MYH9 interacted with GSK-3β to inhibit the expression of GSK-3β protein by promoting its ubiquitination; the downregulation of GSK-3β subsequently promoted the nuclear translocation of β-catenin, enhancing growth, invasion, migration, and temozolomide resistance in glioma cells. Expression levels of HMGA1 and MYH9 were significantly correlated with patient survival and should be considered as independent prognostic factors. Our findings provide new insights into the role of HMGA1 and MYH9 in gliomagenesis and suggest the potential application of HMGA1 and MYH9 in cancer therapy in the future.

MYH9 Facilitates Cell Invasion and Radioresistance in Head and Neck Cancer via Modulation of Cellular ROS Levels by Activating the MAPK-Nrf2-GCLC Pathway

“…Previously, MYH9 has been reported to inhibit cell invasion, presuming (through the modulation of TP53 nuclear retention) to affect p53-responsive genes [ 36 ]. In this study, we demonstrated that MYH9 facilitates cell invasion in HNC ( Figure 1 ), and it has been shown in other cancers as well [ 16 , 17 , 18 , 19 , 20 , 21 ]. Several cellular mechanisms may be involved, including the modulation of epithelial-mesenchymal transition [ 18 , 19 ], focal adhesion assembly [ 20 ], and extracellular matrix ( Figure 1 D).…”

“…Recent reports of MYH9 in other malignant functions have expanded the significance of this molecule. MYH9 may promote cell growth in colorectal cancer [ 17 , 18 ], induce stem-like properties in lung cancer [ 15 ], and reduce chemosensitivity in gliomas and colorectal cancer [ 17 , 21 ]. These effects may relate to regulating stemness-associated markers such as CD44 and CD133 [ 15 , 17 ].…”

“…Moreover, MYH9 reduced the intracellular ROS levels ( Figure 3 A). This lower ROS level may increase cell resistance to irradiation and resistance to other chemotherapeutic drugs [ 17 , 21 ].…”

“…Functionally, MYH9 participates in several malignant processes. Many reports have shown that MYH9 is involved in the facilitation of cancer invasion or metastasis [ 16 , 17 , 18 , 19 , 20 , 21 ], as well as growth promotion [ 17 , 18 ]. Although the oncogenic function of MYH9 is known in most cancers, there are inconsistencies in reports of its role in tumor suppression.…”

HMGA1 Promotes Macrophage Recruitment via Activation of NF-κB-CCL2 Signaling in Hepatocellular Carcinoma

“…HMGA1 is well documented chromatin-associated protein and is known to participate in a myriad of cellular processes including transcriptional regulation, embryonic development, cell cycle progression, DNA damage response, cellular senescence, and mitochondrial function [17,18]. Notably, HMGA1 is also reported to be an oncogene in diverse cancer types [17,[19][20][21][22][23]. For instance, HMGA1 is highly expressed in breast cancer and contributes to angiogenesis via promoting the nuclear localization and transcriptional activity of FOXM1 [24].…”