Wnt signaling in triple-negative breast cancer

Wnt signaling regulates a variety of cellular processes, including cell fate, differentiation, proliferation and stem cell pluripotency. Aberrant Wnt signaling is a hallmark of many cancers. An aggressive subtype of breast cancer, known as triple-negative breast cancer (TNBC), demonstrates dysregulation in canonical and non-canonical Wnt signaling. In this review, we summarize regulators of canonical and non-canonical Wnt signaling, as well as Wnt signaling dysfunction that mediates the progression of TNBC. We review the complex molecular nature of TNBC and the emerging therapies that are currently under investigation for the treatment of this disease

The DEAD box protein p68: a crucial regulator of AKT/FOXO3a signaling axis in oncogenesis

Increased abundance of proto-oncogene AKT and reduced expression of tumor suppressor Forkhead box O3 (FOXO3a), the downstream target of AKT, is frequent in carcinogenesis. Mechanistic insights of AKT gene regulation are limited. DEAD box RNA helicase p68 is overexpressed in various cancers and acts as a transcriptional co-activator of several transcription factors, including β-catenin. Here, we report a novel mechanism of p68-mediated transcriptional activation of AKT, and its ensuing effect on FOXO3a, in colon carcinogenesis. Interestingly, we found that the expression of p68 and AKT exhibits strong positive correlation in normal and colon carcinoma patient samples. In addition, p68 increased both AKT messenger RNA (mRNA) and protein, enhanced AKT promoter activity in multiple colon cancer cell lines. Conversely, p68 knockdown led to reduced AKT mRNA and protein, diminished AKT promoter activity. Here, we demonstrated that p68 occupies AKT promoter with β-catenin as well as nuclear factor-κB (NF-κB) and cooperates with these in potentiating AKT transcription. Furthermore, p68 and FOXO3a expression followed inverse correlation in the same set of colon carcinoma samples. We observed that p68 significantly reduced FOXO3a protein level in an AKTdependent manner. Studies in primary tumors and metastatic lung nodules generated in mice colorectal allograft model, using syngeneic cells stably expressing p68, corroborated our in vitro findings. Hence, a new mechanism of oncogenesis is attributed to p68 by upregulation of AKT and consequent nuclear exclusion and degradation of tumor suppressor FOXO3

The deubiquitylase USP15 regulates topoisomerase II alpha to maintain genome integrity

Ubiquitin-specific protease 15 (USP15) is a widely expressed deubiquitylase that has been implicated in diverse cellular processes in cancer. Here we identify topoisomerase II (TOP2A) as a novel protein that is regulated by USP15. TOP2A accumulates during G2 and functions to decatenate intertwined sister chromatids at prophase, ensuring the replicated genome can be accurately divided into daughter cells at anaphase. We show that USP15 is required for TOP2A accumulation, and that USP15 depletion leads to the formation of anaphase chromosome bridges. These bridges fail to decatenate, and at mitotic exit form micronuclei that are indicative of genome instability. We also describe the cell cycle-dependent behaviour for two major isoforms of USP15, which differ by a short serine-rich insertion that is retained in isoform-1 but not in isoform-2. Although USP15 is predominantly cytoplasmic in interphase, we show that both isoforms move into the nucleus at prophase, but that isoform-1 is phosphorylated on its unique S229 residue at mitotic entry. The micronuclei phenotype we observe on USP15 depletion can be rescued by either USP15 isoform and requires USP15 catalytic activity. Importantly, however, an S229D phospho-mimetic mutant of USP15 isoform-1 cannot rescue either the micronuclei phenotype, or accumulation of TOP2A. Thus, S229 phosphorylation selectively abrogates this role of USP15 in maintaining genome integrity in an isoform-specific manner. Finally, we show that USP15 isoform-1 is preferentially upregulated in a panel of non-small cell lung cancer cell lines, and propose that isoform imbalance may contribute to genome instability in cancer. Our data provide the first example of isoform-specific deubiquitylase phospho-regulation and reveal a novel role for USP15 in guarding genome integrity