The novel metastasis promoter Merm1/Wbscr22 enhances tumor cell survival in the vasculature by suppressing Zac1/p53-dependent apoptosis.

Understanding metastasis is integral to curative cancer treatments. Using a mouse genetic screening model, we identified Merm1/Wbscr22 as a novel metastasis promoter that includes a methyltransferase fold in its structure. Merm1 showed high levels of expression in invasive breast cancer. Ectopic expression of Merm1 in nonmetastatic cells enhanced metastasis formation without affecting cell growth and motility. The intact methyltransferase fold of Merm1 was required for metastasis formation. Interestingly, Merm1 expression promoted cell survival after entrapment in the lung microvasculature. Consistent with these results, knockdown of endogenous Merm1 in tumor cells reduced lung retention and metastasis formation. On the basis of comparative transcriptome analysis, Merm1 expression was negatively correlated with the expression of tumor suppressor Zac1. We confirmed that Merm1 suppressed Zac1 expression with histone H3 methylation at Lys(9) in the Zac1 promoter region. Zac1 can induce apoptosis through its ability to transcriptionally coactivate p53, which regulates apoptosis in the vasculature and is often downregulated in metastasis. We found that Zac1 knockdown reduced the p53-dependent apoptosis that was enhanced by Merm1 knockdown, thereby increasing lung retention of metastatic cells. Our findings show that Merm1 enhances cancer cell survival in the vasculature by suppressing Zac1/p53-dependent apoptosis, thereby enhancing metastasis.