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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 identi ed UBXN2A as a novel tumor suppressor protein in CRCs and hypothesized that UBXN2A suppresses the mTORC2 pathway, thereby inhibiting CRC growth and metastasis. We rst used murine models to show that haploinsu ciency of UBXN2A signi cantly 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 and pharmacological studies 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 signi cantly better survival, and high-grade CRC tissues exhibit decreased UBXN2A protein expression. UBXN2A induction in tumor organoids suppresses the mTORC2 pathway. These ndings provide new insights into the functions of an ubiquitin-like protein by inhibiting a dominant oncogenic pathway in CRC.

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 and pharmacological studies 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. UBXN2A induction in tumor organoids 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.

The medicinal leech, Hirudo verbana, is a powerful model organism for investigating fundamental neurobehavioral processes. The well-documented arrangement and properties of H. verbana’s nervous system allows changes at the level of specific neurons or synapses to be linked to physiological and behavioral phenomena. Juxtaposed to the extensive knowledge of H. verbana’s nervous system is a limited, but recently expanding, portfolio of molecular and multi-omics tools. Together, the advancement of genetic databases for H. verbana will complement existing pharmacological and electrophysiological data by affording targeted manipulation and analysis of gene expression in neural pathways of interest. Here, we present the first draft genome assembly for H. verbana, which is approximately 250 Mbp in size and consists of 61,282 contigs. Whole genome sequencing was conducted using an Illumina sequencing platform followed by genome assembly with CLC-Bio Genomics Workbench and subsequent functional annotation. Ultimately, the diversity of organisms for which we have genomic information should parallel the availability of next generation sequencing technologies to widen the comparative approach to understand the involvement and discovery of genes in evolutionarily conserved processes. Results of this work hope to facilitate comparative studies with H. verbana and provide the foundation for future, more complete, genome assemblies of the leech.