The LIM Protein Ajuba Augments Tumor Metastasis in Colon Cancer

Abstract

Colorectal cancer, along with its high potential for recurrence and metastasis, is a major health burden. Uncovering proteins and pathways required for tumor cell growth is necessary for the development of novel targeted therapies. Ajuba is a member of the LIM domain family of proteins whose expression is positively associated with numerous cancers. Our data shows that Ajuba is highly expressed in human colon cancer tissue and cell lines. Publicly available data from The Cancer Genome Atlas shows a negative correlation between survival and Ajuba expression in patients with colon cancer. To investigate its function, we transduced SW480 human colon cancer cells, with lentiviral constructs to knockdown or overexpress Ajuba protein. The transcriptome of the modified cell lines was analyzed by RNA sequencing. Among the pathways enriched in the differentially expressed genes, were cell proliferation, migration and differentiation. We confirmed our sequencing data with biological assays; cells depleted of Ajuba were less proliferative, more sensitive to irradiation, migrated less and were less efficient in colony formation. In addition, loss of Ajuba expression decreased the tumor burden in a murine model of colorectal metastasis to the liver. Taken together, our data supports that Ajuba promotes colon cancer growth, migration and metastasis and therefore is a potential candidate for targeted therapy.

LIM protein Ajuba promotes liver cell proliferation through its involvement in DNA replication and DNA damage control

“…Moreover, when monocytic cells switch from a proliferative to a differentiated state, Ajuba expression was reduced. Previous data from our lab demonstrated that knockout of Ajuba using CRISPR/Cas9 resulted in non-viable HCC cell lines [40]. This observation, together with the embryonic lethality of CRISPR/Cas9 KO animals has also been supported by Loganathan et al [49], and that Ajuba expression was found during embryogenesis in all embryonic germ layers and within fetal components of the developing placenta [50,51].…”

AJUBA: A regulator of epidermal homeostasis and cancer

“…This AJUBA‐induced YAP increase permits regulation of cyclin D1, Bcl‐xL and GLUT1, influencing mitochondrial potential and glucose uptake to increase cell growth and chemoresistance 105 . Additionally, AJUBA induces metastatic colon cancer by promoting migratory pathways in human colon cancer cells such as Smad1 induced AJUBA/Snail binding to downregulate E‐cadherin expression 106,107 . Furthermore, AJUBA functions as a co‐activator to promote proliferation in pancreatic and breast cancer with the transcription factor SP1 via a feed‐forward loop of downstream targets, EGFR and IGF1R 108 and with ERα by recruiting DBC1 and CBP/p300 to induce expression of TFF1, Greb1 and SGK3 (ERα target genes), 109 respectively.…”

Evidence for AJUBA-catenin-CDH4-linked differentiation resistance of mesenchymal stem cells implies tumorigenesis and progression of head and neck squamous cell carcinoma: a single-cell transcriptome approach

“…As a scaffolding protein, AJUBA plays an essential role in oncogenesis by regulating major signaling pathways, such as Wnt, JAK/STAT, RAS/ERK, and Hippo. It stabilizes adhesion junctions by linking cadherin and α-catenin to cytoskeletal receptor complexes [71] . AJUBA/SP1 forms an SP1 activating feed-forward loop that functions as a biomarker for pancreatic cancer [18] .…”