RRP15 deficiency induces ribosome stress to inhibit colorectal cancer proliferation and metastasis via LZTS2-mediated beta-catenin suppression

Ribosome biogenesis (RiBi) plays a pivotal role in carcinogenesis by regulating protein translation and stress response. Here, we find that RRP15, a nucleolar protein critical for RiBi and checkpoint control, is frequently upregulated in primary CRCs and higher RRP15 expression positively correlated with TNM stage (P < 0.0001) and poor survival of CRC patients (P = 0.0011). Functionally, silencing RRP15 induces ribosome stress, cell cycle arrest, and apoptosis, resulting in suppression of cell proliferation and metastasis. Overexpression of RRP15 promotes cell proliferation and metastasis. Mechanistically, ribosome stress induced by RRP15 deficiency facilitates translation of TOP mRNA LZTS2 (Leucine zipper tumor suppressor 2), leading to the nuclear export and degradation of beta-catenin to suppress Wnt/beta-catenin signaling in CRC. In conclusion, ribosome stress induced by RRP15 deficiency inhibits CRC cell proliferation and metastasis via suppressing the Wnt/beta-catenin pathway, suggesting a potential new target in high-RiBi CRC patients.

Automated summary

Ribosome biogenesis (RiBi) plays a crucial role in carcinogenesis by regulating protein translation and stress response. In this study, it was found that RRP15, a nucleolar protein critical for RiBi and checkpoint control, is frequently upregulated in primary CRCs and its higher expression correlated with TNM stage and poor survival of CRC patients. Silencing RRP15 induced ribosome stress, cell cycle arrest, and apoptosis, resulting in suppression of cell proliferation and metastasis, while overexpression of RRP15 promoted proliferation and metastasis. Mechanistically, RRP15 deficiency led to ribosome stress that facilitated the suppression of Wnt/beta-catenin signaling in CRC.