AKAP9 Upregulation Predicts Unfavorable Prognosis in Pediatric Acute Myeloid Leukemia and Promotes Stemness Properties via the Wnt/β-Catenin Pathway

Abstract

Background: PRKA kinase anchor protein 9 (AKAP9) is a scaffold protein involved in various cellular processes, including cell adhesion, proliferation, differentiation, and apoptosis. Although the oncogenic role of AKAP9 in solid tumors is well elucidated, the functions and mechanisms of AKAP9 in acute myeloid leukemia (AML) are still not understood. Methods: We used the gene expression omnibus (GEO) database (GSE2191) to determine the mRNA expression of AKAP9 in the bone marrow of pediatric AML and healthy patients. We further used the therapeutically available research to generate effective treatments (TARGET) database to elucidate the relationship between AKAP9 expression and clinical outcomes in pediatric patients with AML. In addition, cell proliferation, cell cycle, apoptosis, RT-PCR, and Western blotting assays were applied to reveal the functions of AKAP9 and the underlying mechanisms of AKAP9 silencing in THP1 and HL60 cell lines. Results: AKAP9 is overexpressed in the bone marrow of pediatric AML patients as compared with that of healthy patients. High expression of AKAP9 was found to be a predictor of poor overall survival (OS) and event-free survival (EFS). Using univariate and multivariate survival analyses, we found that high AKAP9 expression is an independent predictor of a worse OS and EFS. Functionally, AKAP9 silencing significantly inhibited AML cell proliferation, and cell cycle progression and promoted apoptosis. Moreover, AKAP9 silencing significantly downregulated the expression of stemness markers and βcatenin. Conclusion: AKAP9 upregulation is a predictor of unfavorable prognosis, promotes stemness, and activates the Wnt/β-catenin pathway in AML patients. AKAP9 may act as a prognostic biomarker of AML in pediatric patients and a future therapeutic target.

Golgi organization is a determinant of stem cell function in the small intestine

“…3i). This is mediated by Akap9, in line with previous findings demonstrating Akap9 role for stemness 36 . Interestingly, ISCs contacting one Paneth cell are found at the edge of the stem cell niche.…”

“…In support of this concept, the Golgi complex was found to reorient to the leading edge during directed cell migration towards a wound 61,62 and during T-cell detection of target cells 63,64 . The stem cell Golgi stack regulator identified here, Akap9, is deregulated in many cancers 36,65 leading to promoted cell migration 35,65 . Therefore, the work presented here may also provide opportunities for understanding and targeting receptor transport in the rapidly remodelling tumour tissue including during cancer metastasis.…”

“…Out of these four, the strongest enrichment in ISCs was noted for A-kinase anchoring protein 9 (Akap9) gene (also known as AKAP350, AKAP450 or CG-NAP) [30][31][32] , which is directly linked with Golgi function and morphology 33 , and its high expression in ISCs was also confirmed by an additional data set 34 . Interestingly, deregulated Akap9 expression is linked to several human cancers 35,36 and Alzheimer's disease 37,38 . Akap9 localizes to the pericentriolar space and cis-Golgi, where it initiates acetylation and nucleation of microtubules 39,40 for example in migrating cells and Golgi 'outposts' of neurons 39,41,42 .…”

Expression of RASSF1A, DIRAS3, and AKAP9 Genes in Thyroid Lesions: Implications for Differential Diagnosis and Prognosis of Thyroid Carcinomas

“…Various genetic alterations of the AKAP9 are known to be primarily associated with cancers of the colorectum [ 34 , 39 ], stomach [ 34 , 38 ], lungs [ 63 ], and breast [ 64 ]. Approximately 10 to 18% of samples carrying the mutated AKAP9 gene are reported, depending on the type of mutation and type of cancer.…”

“…AKAP9 involvement in cancer disease was first mentioned in thyroid cancers, where chromatin rearrangement (paracentric inversion of chromosome 7q) results in the formation of an AKAP9-BRAF fusion protein that affects B-Raf action and constitutively activates the MAPK pathway [ 35 ]. So far, the pro-cancerous activity of AKAP9 has been extensively studied in colorectal cancer [ 36 , 37 ], gastric cancer [ 38 ], and acute myeloid leukaemia [ 39 ], where its action was related to cancer cell proliferation, migration, and invasion [ 32 ], as well as lower survival [ 37 ]. Since the changes in AKAP9 expression were associated with the tumorigenesis process, we question whether they may contribute to the development of thyroid tumours.…”