WWP1 E3 ligase at the crossroads of health and disease.

The E3 ubiquitin ligase WWP1 (WW Domain-containing E3 Ubiquitin Protein Ligase 1) is a member of the HECT (Homologous to the E6-associated protein Carboxyl Terminus) E3 ligase family. It is conserved across several species and plays crucial roles in various physiological processes, including development, cell growth and proliferation, apoptosis, and differentiation. It exerts its functions through ubiquitination or protein-protein interaction with PPXY-containing proteins. WWP1 plays a role in several human diseases, including cardiac conditions, neurodevelopmental, age-associated osteogenic disorders, infectious diseases, and cancers. In solid tumors, WWP1 plays a dual role as both an oncogene and a tumor suppressor, whereas in hematological malignancies such as AML, it is identified as a dedicated oncogene. Importantly, WWP1 inhibition using small molecule inhibitors such as Indole-3-Carbinol (I3C) and Bortezomib or siRNAs leads to significant suppression of cancer growth and healing of bone fractures, suggesting that WWP1 might serve as a potential therapeutic target for several diseases. In this review, we discuss the evolutionary perspective, structure, and functions of WWP1 and its multilevel regulation by various regulators. We also examine its emerging roles in cancer progression and its therapeutic potential. Finally, we highlight WWP1's role in normal physiology, contribution to pathological conditions, and therapeutic potential for cancer and other diseases.

AMPK-induced novel phosphorylation of RUNX1 inhibits STAT3 activation and overcome imatinib resistance in chronic myelogenous leukemia (CML) subjects.

Imatinib resistance remains an unresolved problem in CML disease. Activation of JAK2/STAT3 pathway and increased expression of RUNX1 have become one reason for development of imatinib resistance in CML subjects. Metformin has gained attention as an antileukemic drug in recent times. However, the molecular mechanism remains elusive. The present study shows that RUNX1 is a novel substrate of AMP-activated kinase (AMPK), where AMPK phosphorylates RUNX1 at Ser 94 position. Activation of AMPK by metformin could lead to increased cytoplasmic retention of RUNX1 due to Ser 94 phosphorylation. RUNX1 Ser 94 phosphorylation resulted in increased interaction with STAT3, which was reflected in reduced transcriptional activity of both RUNX1 and STAT3 due to their cytoplasmic retention. The reduced transcriptional activity of STAT3 and RUNX1 resulted in the down-regulation of their signaling targets involved in proliferation and anti-apoptosis. Our cell proliferation assays using in vitro resistant cell line models and PBMCs isolated from CML clinical patients and normal subjects demonstrate that metformin treatment resulted in reduced growth and improved imatinib sensitivity of resistant subjects.

Keep your eyes peeled for long noncoding RNAs: Explaining their boundless role in cancer metastasis, drug resistance, and clinical application.

Cancer metastasis and drug resistance are two major obstacles in the treatment of cancer and therefore, the leading cause of cancer-associated mortalities worldwide. Hence, an in-depth understanding of these processes and identification of the underlying key players could help design a better therapeutic regimen to treat cancer. Earlier thought to be merely transcriptional junk and having passive or secondary function, recent advances in the genomic research have unravelled that long noncoding RNAs (lncRNAs) play pivotal roles in diverse physiological as well as pathological processes including cancer metastasis and drug resistance. LncRNAs can regulate various steps of the complex metastatic cascade such as epithelial-mesenchymal transition (EMT), invasion, migration and metastatic colonization, and also affect the sensitivity of cancer cells to various chemotherapeutic drugs. A substantial body of literature for more than a decade of research evince that lncRNAs can regulate gene expression at different levels such as epigenetic, transcriptional, posttranscriptional, translational and posttranslational levels, depending on their subcellular localization and through their ability to interact with DNA, RNA and proteins. In this review, we mainly focus on how lncRNAs affect cancer metastasis by modulating expression of key metastasis-associated genes at various levels of gene regulation. We also discuss how lncRNAs confer cancer cells either sensitivity or resistance to various chemo-therapeutic drugs via different mechanisms. Finally, we highlight the immense potential of lncRNAs as prognostic and diagnostic biomarkers as well as therapeutic targets in cancer.