Ubiquitin-Related Modifier 1 (URM-1) Modulates Cx43 in Breast Cancer Cell Lines.

Gap-junction-forming connexins are exquisitely regulated by post-translational modifications (PTMs). In particular, the PTM of connexin 43 (Cx43), a tumor suppressor protein, regulates its turnover and activity. Here, we investigated the interaction of Cx43 with the ubiquitin-related modifier 1 (URM-1) protein and its impact on tumor progression in two breast cancer cell lines, highly metastatic triple-negative MDA-MB-231 and luminal breast cancer MCF-7 cell lines. To evaluate the subsequent modulation of Cx43 levels, URM-1 was downregulated in these cells. The transcriptional levels of epithelial-to-mesenchymal transition (EMT) markers and the metastatic phenotype were assessed. We demonstrated that Cx43 co-localizes and interacts with URM-1, and URMylated Cx43 was accentuated upon cellular stress. The significant upregulation of small ubiquitin-like modifier-1 (SUMO-1) was also observed. In cells with downregulated URM-1, Cx43 expression significantly decreased, and SUMOylation by SUMO-1 was affected. The concomitant expression of EMT markers increased, leading to increased proliferation, migration, and invasion potential. Inversely, the upregulation of URM-1 increased Cx43 expression and reversed EMT-induced processes, underpinning a role for this PTM in the observed phenotypes. This study proposes that the URMylation of Cx43 in breast cancer cells regulates its tumor suppression properties and contributes to breast cancer cell malignancy.

Regenerative Medicine for Polycystic Ovary Syndrome: Stem Cell-Based Therapies and Brown Adipose Tissue Activation.

Polycystic ovary syndrome (PCOS) is a pathological condition prevalent among women of reproductive age: it is associated with varied etiological factors (lifestyle, genetic, environmental…) and characterized by an increased polycystic morphology of the ovaries leading to disturbances in the menstrual cycle and its correlated infertility. Interconnections between PCOS, obesity, and insulin resistance have been recently investigated thoroughly in the scientific community; these findings directed PCOS therapies into unraveling possibilities to target insulin resistance and central adiposity as efficient treatment. On the other hand, brown adipose tissue is known to possess a thermogenic activity that increases lipolysis and directly attenuates fat deposition. Therefore, brown adipose tissue activation lands itself as a potential target for reducing obesity and its induced insulin resistance, subsequently rescuing PCOS phenotypes. In addition, regenerative medicine has proven efficacy in resolving PCOS-associated infertility and its metabolic symptoms. In particular, many stem/progenitor cells have been verified to possess the differentiation capacity into functional brown adipocytes. Thus, throughout this review, we will discuss the different brown adipose tissue activation strategies and stem-cell-based therapies applied to PCOS models and the possible combination of both therapeutic approaches to synergistically act on the activation of brown adipose tissue and attenuate PCOS-correlated infertility and retract the consequences of the metabolic syndrome on the physiological state of patients.