Ryanodine receptor 2 promotes colorectal cancer metastasis by the ROS/BACH1 axis.

KRAS proto-oncogene, GTPase (KRAS)-mutant metastatic colorectal cancer (mCRC) lacks targeted therapy because the underlying mechanism remains obscure. Based on bioinformatic analysis, this study aims to elucidate a potential gene target for which an approved drug is available , and to further reveal the function as well as the underlying mechanism of the candidate gene. Here, we identified that ryanodine receptor 2 (RyR2) expression was upregulated in KRAS-mutant mCRC, and that this promoted cancer cell metastasis. S107, an approved drug to inhibit calcium release from RyR2 in the clinic, inhibited cancer cell metastasis both in vitro and in vivo. High expression of RyR2 predicts poor survival in our patient cohort. CRC patients with serosa invasion and vascular tumor thrombus are characterized by high RyR2 expression. Analysis of expression profiles upon RyR2 knockdown and inhibition reveals a set of metastasis-related molecules, and identifies BTB domain and CNC homolog 1 (BACH1) as the main transcription factor regulated by RyR2. RyR2 regulates cellular reactive oxygen species (ROS) levels, which activates nuclear factor erythroid 2-related factor 2 (Nrf2; also known as NFE2L2) and HMOX1 expression, and thus BACH1 accumulation. Collectively, this study provides evidence that the RyR2/ROS/BACH1 axis may be a potential target to intervene with CRC metastasis.