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

Sanam Sane, Rekha Srinivasan, Rashaun A. Potts, Morgan Eikanger, Diana Zagirova, Jessica Freeling, Casey A. Reihe, Ryan M. Antony, Brij K. Gupta, Douglas Lynch, Jonathan Bleeker, Hassan Turaihi, Angela Pillatzki, Wei Zhou, Xu Luo, Michael Linnebacher, Diing Agany, Etienne Gnimpieba Zohim, Lisa E. Humphrey, Adrian R. BlackKhosrow Rezvani

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1763-1776
Number of pages14
JournalOncogene
Volume42
Issue number21
DOIs
StatePublished - May 22 2023

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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