Deacetylation-dependent stabilization of VASH2 drives YAP activation leading to colorectal cancer progression and chemoresistance

Colorectal cancer (CRC) is a common and fatal malignancy, with chemoresistance posing a formidable challenge. Understanding the mechanisms driving CRC progression and chemoresistance is essential for new therapy development. Although vasohibin-2 (VASH2) is known for its pro-angiogenic role, its non-angiogenic functions in CRC are less well understood. This study aimed to clarify VASH2’s role and mechanisms in CRC progression and chemosensitivity, and to delineate the regulatory pathway controlling its expression. Analysis of public databases and RNA sequencing data revealed that VASH2 is significantly upregulated in CRC and correlated with poor chemosensitivity. Increased VASH2 expression was also confirmed in clinical CRC tissue samples. Based on these findings, stable VASH2-knockdown CRC cell lines were established. In vitro and in vivo assays demonstrated that VASH2 knockdown suppressed malignant growth and increased chemosensitivity. Mechanistically, VASH2 promoted α-tubulin detyrosination, which is associated with reduced YAP phosphorylation and degradation. Furthermore, histone deacetylase 10 (HDAC10) was identified as a critical stabilizer of VASH2, inhibiting its proteasomal degradation and increasing VASH2 levels. Collectively, these findings indicate that elevated VASH2 enhances α-tubulin detyrosination and increases YAP protein levels, thereby driving CRC progression and chemoresistance. Furthermore, HDAC10 enhances VASH2 stability by preventing its proteasomal degradation, leading to its upregulation in CRC. These results reveal a novel VASH2-driven oncogenic pathway and provide a foundation for targeting VASH2 in CRC therapy. Image illustrating the mechanism of the HDAC10-VASH2 axis influences YAP activation to regulate CRC growth and chemosensitivity. Our findings reveal that HDAC10-mediated deacetylation of VASH2 at lysine 281 suppresses its proteasomal degradation, thereby stabilizing VASH2 expression in CRC. This upregulation enhances α-tubulin detyrosination, facilitates YAP activation, and ultimately contributes to accelerating tumor progression and reducing chemosensitivity.