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.
Highlights
Colorectal cancer (CRC) is the third most common malignancy, with around 1.8 million newly diagnosed cases worldwide annually [1]
To investigate the role Autophagy-related protein 9B (ATG9B) plays in cancer, we analysed the transcriptional datasets assembled from clinical samples in public database ONCOMINE and discovered that the transcriptional levels of ATG9B were dramatically increased in various cancers, especially in CRC (Fig. S1A, B)
We detected the expression of ATG9B protein in paraffin-embedded CRC and normal tissue and found a significantly higher expression of ATG9B in CRC tissue than in normal mucosa (Fig. 1E, F), which was positively associated with high risk of tumour lymph, distal metastasis and advanced Duke’s stage (Fig. 1G, H and Supplementary Table S1)
Summary
Colorectal cancer (CRC) is the third most common malignancy, with around 1.8 million newly diagnosed cases worldwide annually [1]. Forty percent of cases develop metastasis, which is the major reason for the high mortality of CRC [2, 3]. Tumour metastasis is a sophisticated biological process, and the molecular mechanism still cannot be fully explained. Unravelling the molecular mechanisms underlying CRC metastasis is vital to develop early intervention strategies, especially for individuals with high risk of metastasis. Autophagy is the process to maintain cellular homoeostasis and is regulated by almost 40 autophagy-related proteins (ATGs). ATGs play important roles in autophagy and contribute prominently to tumour metastasis [4]. We identified ATG9B as a downstream target of MALAT-1 [8], which is reported to play an important role in CRC metastasis. The role and mechanism of ATG9B in CRC metastasis remain unclear
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