The transcriptional coactivator WBP2 primes triple-negative breast cancer cells for responses to Wnt signaling via the JNK/Jun kinase pathway

Abstract

The transcriptional coactivator WW domain-binding protein 2 (WBP2) is an emerging oncogene and serves as a node between the signaling protein Wnt and other signaling molecules and pathways, including epidermal growth factor receptor, estrogen receptor/progesterone receptor, and the Hippo pathway. The upstream regulation of WBP2 is well-studied, but its downstream activity remains unclear. Here, we elucidated WBP2's role in triple-negative breast cancer (TNBC), in which Wnt signaling is predominantly activated. Using RNAi coupled with RNA-Seq and MS analyses to identify Wnt/WBP2-and WBP2-dependent targets in MDA-MB-231 TNBC cells, we found that WBP2 is required for the expression of a core set of genes in Wnt signaling. These included AXIN2, which was essential for Wnt/WBP2-mediated breast cancer growth and migration. WBP2 also regulated a much larger set of genes and proteins independently of Wnt, revealing that WBP2 primes cells to Wnt activity by up-regulating G protein pathway suppressor 1 (GPS1) and TRAF2-and NCK-interacting kinase (TNIK). GPS1 activated the c-Jun N-terminal kinase (JNK)/Jun pathway, resulting in a positive feedback loop with TNIK that mediated Wnt-induced AXIN2 expression. WBP2 promoted TNBC growth by integrating JNK with Wnt signaling, and its expression profoundly influenced the sensitivity of TNBC to JNK/TNIK inhibitors. In conclusion, WBP2 links JNK to Wnt signaling in TNBC. GPS1 and TNIK are constituents of a WBP2initiated cascade that primes responses to Wnt ligands and are also important for TNBC biology. We propose that WBP2 is a potential drug target for JNK/TNIK-based precision medicine for managing TNBC.

The emerging roles of WBP2 oncogene in human cancers

“…It is conceivable that WBP2 possesses nonnuclear functions that remain to be discovered. This notion is supported by the results arising from the interrogation of the proteomics data against the RNA-seq data which showed that 30% of the WBP2-target proteins were regulated at the mRNA level, whereas the majority were regulated at the posttranscriptional or posttranslational level [33].…”

“…A glimpse into the global mode of action of WBP2 in Wnt signaling was revealed through the work of our group in which RNA-seq was employed to ascertain the pervasiveness of WBP2 in Wnt signaling [33]. More than 80% of the Wntinduced genes in MDA-MB-231 TNBC cells were demonstrated to be dependent on WBP2.…”

“…Analysis of the gene copy number alterations and mRNA expression of the WBP2 gene in multiple large-scale breast cancer datasets such as The Cancer Genome Atlas (TCGA) [48] and METABRIC [49,50] indicated that WBP2 is frequently amplified (4.1-25%) or gained (0-31.7%) in breast cancer patients, whereas deletion was barely present [33]. Other cancer types that showed upregulation of WBP2 gene expression in the TCGA database include kidney renal papillary cell carcinoma, kidney renal clear cell carcinoma, and thyroid carcinoma.…”

“…Enrichment analysis of the list of genes in the amplified region of C17q using the PANTHER gene ontology database [88] indicates that WBP2 participates in Wnt, EGFR, NF-κB/inflammation, and integrin signaling pathways (Fig. 7), of which WBP2 protein has already been implicated in the former two [11,13,33]. NF-κB pathway is a well-characterized transduction system tightly associated with cancer hallmarks [89].…”

NEDD9 promotes invasion and migration of colorectal cancer cell line HCT116 via JNK/EMT

“…A review of the literature reveals the relevant situation downstream of JNK. For example, IL-2/sorafenib can affect tumor survival, growth and mobility through JNK-TAZ pathways (41), GPS1 can activate the c-Jun N-terminal kinase (JNK)/Jun pathway to affect breast cancer growth and migration (42), Saikosaponin D induced apoptosis via the activation of TGFα-JNK-p53 (43), Thymoquinone inhibits the metastasis through activation of JNK-p38 (44), JNK-ELK1 The pathway can also have an effect on the tumor (45). These are the pathways already known downstream of JNK, but there must be downstream pathways that have not been studied.…”