Transcription Factor HOXC11 Drives Colorectal Cancer Progression and Metastasis via CAMK2A‐Dependent CXCL5 Upregulation

ABSTRACT

Colorectal cancer (CRC) remains a leading cause of cancer mortality, and the molecular drivers of progression and distant metastasis are incompletely understood. By integrating differential expression and survival analyses of TCGA CRC cohorts with HOX family genes, we identified HOXC11 as a key metastasis‐associated factor. HOXC11 was markedly upregulated in CRC tissues and cell lines, with higher expression in metastatic lesions than in primary tumors, and elevated HOXC11 correlated with poor patient prognosis. HOXC11 functionally increased CRC cell proliferation, migration, and invasion in vitro and facilitated tumor growth and metastasis in vivo. Mechanistically, HOXC11 directly bound to the CAMK2A promoter and transactivated CAMK2A, leading to increased phosphorylated CAMK2A and initiation of the NF‐κB pathway, which facilitated p65 nuclear translocation and induced CXCL5 expression to drive CRC progression. Conversely, CXCL5 signaling through CXCR2 upregulated HOXC11 via the ERK1/2‐SP1 axis, forming a positive feedback loop. Notably, combined inhibition of CAMK2A (KN‐93) and CXCR2 (SB265610) significantly attenuated HOXC11‐mediated proliferation and metastasis. Collectively, these findings define a HOXC11–CAMK2A–NF‐κB–CXCL5 circuit as a potential therapeutic target in CRC.