UBXN2A suppresses the Rictor-mTORC2 signaling pathway, an established tumorigenic pathway in human colorectal cancer.

The mTORC2 pathway plays a critical role in promoting tumor progression in human colorectal cancer (CRC). The regulatory mechanisms for this signaling pathway are only partially understood. We previously identified UBXN2A as a novel tumor suppressor protein in CRCs and hypothesized that UBXN2A suppresses the mTORC2 pathway, thereby inhibiting CRC growth and metastasis. We first used murine models to show that haploinsufficiency of UBXN2A significantly increases colon tumorigenesis. Induction of UBXN2A reduces AKT phosphorylation downstream of the mTORC2 pathway, which is essential for a plethora of cellular processes, including cell migration. Meanwhile, mTORC1 activities remain unchanged in the presence of UBXN2A. Mechanistic studies revealed that UBXN2A targets Rictor protein, a key component of the mTORC2 complex, for 26S proteasomal degradation. A set of genetic, pharmacological, and rescue experiments showed that UBXN2A regulates cell proliferation, apoptosis, migration, and colon cancer stem cells (CSCs) in CRC. CRC patients with a high level of UBXN2A have significantly better survival, and high-grade CRC tissues exhibit decreased UBXN2A protein expression. A high level of UBXN2A in patient-derived xenografts and tumor organoids decreases Rictor protein and suppresses the mTORC2 pathway. These findings provide new insights into the functions of an ubiquitin-like protein by inhibiting a dominant oncogenic pathway in CRC.

Systemic inhibition of neddylation by 3-day MLN4924 treatment regime does not impair autophagic flux in mouse hearts and brains.

Beyond helping the cell survive from energy starvation via self-eating a portion of cytoplasm, macroautophagy is also capable of targeted removal of defective organelles or cytoplasmic aberrant protein aggregates, thereby playing an important role in quality control in the cell. Impaired or suppressed macroautophagy activity is associated with the progression from a large subset of heart diseases to heart failure and with the development of the vast majority of, if not all, neurodegenerative diseases, the leading causes of death and disability in humans. Hence, a better understanding of the impact of existing and upcoming pharmacotherapies on macroautophagy in the heart and brain will undoubtedly benefit the search for safer and more effective treatment to improve human health. Neddylation is a recently recognized posttranslational modification process that modifies a subset of cellular proteins and is, by virtue of regulating Cullin-RING ligases, essential to ~20% ubiquitin-proteasome system (UPS)-mediated protein degradation. MLN4924 (Pevonedistat), a specific inhibitor of neddylation that promises to become a new anti-malignancy agent, is capable of inhibiting UPS-mediated progression of the cell cycle and activating macroautophagy in cancer cells. However, no reported study has tested the impact of systemic inhibition of neddylation on autophagic activity in a post-mitotic organ such as the heart and brain. This study was conducted to fill this gap. Sixteen GFP-LC3 transgenic mice of mixed sexes were divided equally into either MLN4924-treated or vehicle-treated groups and were treated respectively with MLN4924 (30 mg/kg, s.c., twice a day × 3 days) or equal volume of solvent. The resultant changes in myocardial levels of neddylated cullin 1 as well as autophagic flux in cardiac and brain tissues were assessed. The effectiveness of the MLN4924 regime was verified by myocardial accumulation of neddylated cullin 1. Myocardial LC3-II flux and free GFP levels were comparable between the MLN4924 and the vehicle groups whereas the protein level of p62, a bona fide substrate of macroautophagy, in the brain was significantly decreased by the MLN4924 treatment. Our data suggest that systemic inhibition of neddylation by a 3-day MLN4924 treatment regime does not suppress macroautophagy activities in the heart and brain.