FAM46C controls antibody production by the polyadenylation of Ig mRNAs and inhibits cell migration in multiple myeloma

ABSTRACT: FAM46C, which is frequently mutated in multiple myeloma (MM), has recently been shown to encode a non-canonical poly(A) polymerase (ncPAP). However, its target mRNAs and its role in MM pathogenesis remain largely unknown. Using CRISPR-Cas9 technology and gene expression analysis we found that inactivation of FAM46C in MM downregulates immunoglobulins (Igs) and several mRNAs encoding ER-resident proteins, including some involved in unfolded protein responses (UPRs), such as PDIA6, ERP44 and EDEM2, and others that affect glycosylation, such as SSR4, AGA and DDOST. We show that FAM46C expression is induced during PC differentiation and that Ig mRNAs encoding heavy and light chains are direct substrates of the ncPAP, as revealed by poly(A) tail-length determination assays. The absence of the ncPAP results in Ig mRNA poly(A) tail-shortening, leading to a reduction in mRNA and protein abundance. On the other hand, loss of FAM46C upregulates metastasis-associated lncRNA MALAT1 and results in a sharp increase in the migration ability of MM cells. This phenotype depends mainly on the activation of PI3K/Rac1 signaling in FAM46C knockout cells since treatment with specific inhibitors substantially reduces cell mobility. This finding may have significant therapeutic implications. In conclusion, our results identify Ig mRNAs as targets of FAM46C, reveal an important function of this protein during PC maturation to increase antibody production, and show that its inactivation in MM increases cell migration and invasion, which might explain the poor prognosis of MM patients with FAM46C alterations and its role as a tumor suppressor.

ORGANISM(S): Homo sapiens

PROVIDER: GSE114984 | GEO | 2020/04/10

REPOSITORIES: GEO