4.7 Article

Diverse Ras-related GTPase DIRAS2, downregulated by PSMD2 in a proteasome-mediated way, inhibits colorectal cancer proliferation by blocking NF-κB signaling

Journal

INTERNATIONAL JOURNAL OF BIOLOGICAL SCIENCES
Volume 18, Issue 3, Pages 1039-1050

Publisher

IVYSPRING INT PUBL
DOI: 10.7150/ijbs.68312

Keywords

DIRAS family GTPase 2; 26S proteasome non-ATPase regulatory subunit 2; colorectal cancer; tumorigenesis; NF-kappa B

Funding

  1. National Natural Science Foundation of China [81972716]

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This study identified the crucial roles of DIRAS2 in colorectal cancer, suggesting its potential as a tumor-suppressor gene and revealing a distinct mechanism in CRC tumorigenesis. Downregulation of DIRAS2 expression is associated with poor prognosis in CRC patients.
Colorectal cancer (CRC) is the most common gastrointestinal cancer, with a high mortality rate but limited therapeutic targets. DIRAS family GTPase 2 (DIRAS2) is a member of the Ras-related small G-protein family whose biological functions and underlying mechanism in CRC remain poorly understood. In this study, we identified the crucial roles of DIRAS2 in CRC. DIRAS2 expression was downregulated in CRC and closely correlated with poor prognosis. Functionally, DIRAS2 inhibited CRC cell proliferation and affected cell-cycle protein expression. Mechanistically, DIRAS2 blocked nuclear factor kappa light-chain enhancer of activated B-cell signaling pathways, inducing G0/G1 arrest. Moreover, DIRAS2 interacted with 26S proteasome non-ATPase regulatory subunit 2, which facilitates the degradation of DIRAS2 in a proteasome-mediated way. Together, these results demonstrate potential functions of DIRAS2 as a tumor-suppressor gene in CRC and reveal a distinct mechanism of DIRAS2 in CRC tumorigenesis, indicating its role as a potential biomarker and target for CRC therapy.

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