Development of Inhibitors, Probes, and PROTAC Provides a Complete Toolbox to Study PARK7 in the Living Cell.

The integration of diverse chemical tools like small-molecule inhibitors, activity-based probes (ABPs), and proteolysis targeting chimeras (PROTACs) advances clinical drug discovery and facilitates the exploration of various biological facets of targeted proteins. Here, we report the development of such a chemical toolbox for the human Parkinson disease protein 7 (PARK7/DJ-1) implicated in Parkinson's disease and cancers. By combining structure-guided design, miniaturized library synthesis, and high-throughput screening, we identified two potent compounds, and , inhibiting PARK7 and in cells by covalently and selectively targeting its critical residue, Cys106.

EGF-SNX3-EGFR axis drives tumor progression and metastasis in triple-negative breast cancers.

Epidermal growth factor receptor (EGFR) has critical roles in epithelial cell physiology. Over-expression and over-activation of EGFR have been implicated in diverse cancers, including triple-negative breast cancers (TNBCs), prompting anti-EGFR therapies. Therefore, developing potent therapies and addressing the inevitable drug resistance mechanisms necessitates deciphering of EGFR related networks.

Alternative Polyadenylation Patterns for Novel Gene Discovery and Classification in Cancer.

Certain aspects of diagnosis, prognosis, and treatment of cancer patients are still important challenges to be addressed. Therefore, we propose a pipeline to uncover patterns of alternative polyadenylation (APA), a hidden complexity in cancer transcriptomes, to further accelerate efforts to discover novel cancer genes and pathways. Here, we analyzed expression data for 1045 cancer patients and found a significant shift in usage of poly(A) signals in common tumor types (breast, colon, lung, prostate, gastric, and ovarian) compared to normal tissues.

3'UTR shortening and EGF signaling: implications for breast cancer.

Alternative polyadenylation (APA) plays a role in gene expression regulation generally by shortening of 3'UTRs (untranslated regions) upon proliferative signals and relieving microRNA-mediated repression. Owing to high proliferative indices of triple negative breast cancers (TNBCs), we hypothesized APA to cause 3'UTR length changes in this aggressive subgroup of breast cancers. Our probe-based meta-analysis approach identified 3'UTR length alterations where the significant majority was shortening events (∼70%, 113 of 165) of mostly proliferation-related transcripts in 520 TNBC patients compared with controls.

ARID3B expression in primary breast cancers and breast cancer-derived cell lines.

Background: ARID3B (AT-rich interaction domain 3) is a member of the family of ARID proteins, which constitutes evolutionarily conserved transcription factors implicated in normal development, differentiation, cell cycle regulation and chromatin remodeling. In addition, ARID3B has been linked to cellular immortalization, epithelial-mesenchymal transition (EMT) and tumorigenesis. Given the emerging role of ARID3B in tumor development, we examined its expression in primary patient-derived breast cancer samples and breast cancer-derived cell lines.