Journal of translational medicine · 2025
CX26 promotes pancreatic cancer progression by competitively inhibiting interaction of c-Myc with PSMD2 and enhancing c-Myc stability.
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He Cheng, Tang Chuanyu, Guo Jie, Yin Xiangyi, Zhu Qing, Fang Chihua
Аннотация
BACKGROUND: Pancreatic cancer (PC) is highly aggressive and fatal and has dismal prognostic outcomes, primarily due to its late-stage diagnosis and limited effective treatments. The molecular mechanisms triggering PC progression are largely unclear. This study investigated how CX26 contributes to pancreatic cancer development and its potential as a therapeutic target.
METHODS: CX26 expression in PC and its clinical significance were examined through bioinformatics analysis. The biological functions of CX26 in PC cells were explored via colony formation, CCK-8, and proteomic analysis. To explore the mechanisms by which CX26 regulates c-Myc stability, co-immunoprecipitation, immunofluorescence, and molecular docking were utilized to investigate the interactions among CX26, PSMD2, and c-Myc. Additionally, subcutaneous xenografts in nude mice were applied to assess the impact of CX26 on PC progression in vivo.
RESULTS: Bioinformatics analysis indicated the upregulation of CX26 in PC tissues. In addition, CX26 expression was closely related to dismal prognostic outcomes. Further study revealed that CX26 promotes PC progression in vitro and in vivo. Proteomic analysis identified c-Myc as the key downstream target of CX26. Mechanistically, CX26 indirectly regulated c-Myc stability via PSMD2 rather than directly interacting with c-Myc. Moreover, CX26 competes with c-Myc to bind to the Armadillo-like helical domain of PSMD2, thereby preventing c-Myc proteasomal degradation.
CONCLUSIONS: This study suggests that CX26 facilitates PC progression by stabilizing c-Myc through competitively inhibiting the binding of PSMD2 to c-Myc. Given the challenges in directly inhibiting c-Myc, this novel regulatory mechanism provides valuable insights into PC biology and reveals that targeting CX26 is a possible way to promote c-Myc degradation and suppress PC growth.
METHODS: CX26 expression in PC and its clinical significance were examined through bioinformatics analysis. The biological functions of CX26 in PC cells were explored via colony formation, CCK-8, and proteomic analysis. To explore the mechanisms by which CX26 regulates c-Myc stability, co-immunoprecipitation, immunofluorescence, and molecular docking were utilized to investigate the interactions among CX26, PSMD2, and c-Myc. Additionally, subcutaneous xenografts in nude mice were applied to assess the impact of CX26 on PC progression in vivo.
RESULTS: Bioinformatics analysis indicated the upregulation of CX26 in PC tissues. In addition, CX26 expression was closely related to dismal prognostic outcomes. Further study revealed that CX26 promotes PC progression in vitro and in vivo. Proteomic analysis identified c-Myc as the key downstream target of CX26. Mechanistically, CX26 indirectly regulated c-Myc stability via PSMD2 rather than directly interacting with c-Myc. Moreover, CX26 competes with c-Myc to bind to the Armadillo-like helical domain of PSMD2, thereby preventing c-Myc proteasomal degradation.
CONCLUSIONS: This study suggests that CX26 facilitates PC progression by stabilizing c-Myc through competitively inhibiting the binding of PSMD2 to c-Myc. Given the challenges in directly inhibiting c-Myc, this novel regulatory mechanism provides valuable insights into PC biology and reveals that targeting CX26 is a possible way to promote c-Myc degradation and suppress PC growth.