The Novel Metastasis Promoter Merm1/Wbscr22 Enhances Tumor Cell Survival in the Vasculature by Suppressing Zac1/p53-Dependent Apoptosis

Abstract

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. Cancer Res; 71(3); 1146-55. Ó2010 AACR.

Structural and functional studies of Bud23–Trm112 reveal 18S rRNA N 7 -G1575 methylation occurs on late 40S precursor ribosomes

“…Finally, WBSCR22, the human Bud23 ortholog, is highly expressed in invasive breast cancers, and the integrity of its SAM binding motif is required to confer metastatic properties to otherwise nonmetastatic cells (28). Furthermore, silencing of WBSCR22 results in specifically increased lethality of myeloma cells, identifying it as a potential target for cancer therapy (29).…”

“…WBSCR22 has been identified as a cancer metastasis promoter, a breast cancer biomarker, and a putative therapeutic target in myeloma (28,29). WBSCR22 is also one of the multiple genes associated with the neurodevelopmental disorder William-Beuren syndrome (30).…”

WBSCR22/Merm1 is required for late nuclear pre-ribosomal RNA processing and mediates N7-methylation of G1639 in human 18S rRNA

“…Depletion of WBSCR22 results in nuclear accumulation of 3 ′ -extended 18SE pre-rRNAs, suggesting an important function of WBSCR22 in facilitating the 3 ′ -5 ′ -trimming of 18SE prerRNAs, enabling nuclear export of pre-40S particles. WBSCR22 is associated not only with Williams-Beuren syndrome but also cancer progression and the inflammatory response (Nakazawa et al 2011;Jangani et al 2014). While the hemizygous deletion of WBSCR22 in Williams-Beuren syndrome is unlikely to correlate with ribosome biogenesis defects, it will be interesting to see whether the key role of WBSCR22 in ribosome production underlies its links to other cellular pathways.…”

“…Based on sequence similarity, WBSCR22 was suggested to contain an S-adenosyl-methionine binding site and to belong to the family of Rossman-fold methyltransferases, but no methyltransferase activity has been reported so far. Elevated expression of WBSCR22 was detected in invasive breast cancer and the protein was shown to enhance metastasis formation by suppression of the Zac1/p53-induced apoptosis, accompanied by histone 3 lysine 9 (H3K9) methylation at the Zac1 promoter (Nakazawa et al 2011). A loss of WBSCR22 was detected in inflammatory and neoplastic lung pathologies and the protein has been linked to glucocorticoid receptor regulation of histone modification (Jangani et al 2014).…”

Genome-Wide Study of Hypomethylated and Induced Genes in Patients with Liver Cancer Unravels Novel Anticancer Targets

“…WBSCR22 that contains a methyltransferase domain and is part of the chromosomal region deleted in Williams syndrome, a multisystem developmental disorder (17), was shown to be overexpressed in invasive breast cancer. Ectopic expression of WBSCR22 in nonmetastatic cells enhances metastasis formation without affecting cell growth and motility and its knockdown in tumor cells reverses metastasis in breast cancer cells (18). SENP6 is member of a family of sumoylation proteases (19) that were shown to be elevated in several kinds of tumors and contribute to cancer through altering the balance of sumoylation of important transcription regulators (20).…”