MYH9-dependent polarization of ATG9B promotes colorectal cancer metastasis by accelerating focal adhesion assembly

Abstract

Tumour metastasis is a major reason accounting for the poor prognosis of colorectal cancer (CRC), and the discovery of targets in the primary tumours that can predict the risk of CRC metastasis is now urgently needed. In this study, we identified autophagy-related protein 9B (ATG9B) as a key potential target gene for CRC metastasis. High expression of ATG9B in tumour significantly increased the risk of metastasis and poor prognosis of CRC. Mechanistically, we further find that ATG9B promoted CRC invasion mainly through autophagy-independent manner. MYH9 is the pivotal interacting protein for ATG9B functioning, which directly binds to cytoplasmic peptide segments aa368–411 of ATG9B by its head domain. Furthermore, the combination of ATG9B and MYH9 enhance the stability of each other by decreasing their binding to E3 ubiquitin ligase STUB1, therefore preventing them from ubiquitin-mediated degradation, which further amplified the effect of ATG9B and MYH9 in CRC cells. During CRC cell invasion, ATG9B is transported to the cell edge with the assistance of MYH9 and accelerates focal adhesion (FA) assembly through mediating the interaction of endocytosed integrin β1 and Talin-1, which facilitated to integrin β1 activation. Clinically, upregulated expression of ATG9B in human CRC tissue is always accompanied with highly elevated expression of MYH9 and associated with advanced CRC stage and poor prognosis. Taken together, this study highlighted the important role of ATG9B in CRC metastasis by promoting focal adhesion assembly, and ATG9B together with MYH9 can provide a pair of potential therapeutic targets for preventing CRC progression.

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).…”

“…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.…”

“…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.…”

Stationed or Relocating: The Seesawing EMT/MET Determinants from Embryonic Development to Cancer Metastasis

“…Integrin α5 can regulate migration and invasion through the FAK/STAT3/AKT axis, and it also contributes to cell resistance to chemotherapy-related treatment [149]. Moreover, multiple molecules can be observed to regulate cells by crosstalk integrin-related signaling, such as Myosin Heavy Chain 9 (MYH9), Rab11, and Wnt5a [150][151][152], especially the latter, as the paracrine factors involved in EMT/MET have been found to modulate the ITGAV level in ovarian cancer [152]. Interestingly, the interaction of osteopontin and integrin αvβ3 can accelerate cellular uptake of glucose to improve cell migration ability [153].…”

High Expression of circ_0001821 Promoted Colorectal Cancer Progression Through miR-600/ISOC1 Axis

“…CRC has a good prognosis if it can be detected earlier and treated surgically (Li et al 2021). If the disease is already at an advanced stage, it can be treated with surgery, but the postoperative complications are also very frightening and directly related to the mortality of CRC (Bonney et al 2021;Henderson et al 2021;Kok et al 2021;Zhong et al 2021). However, the molecular mechanism of CRC in the pathogenesis was not clear.…”