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

Abstract

FAM46C, 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 mostly unknown. Using CRISPR‐Cas9 technology and gene expression analysis, we found that the inactivation of FAM46C in MM down‐regulates immunoglobulins (Igs) and several mRNAs encoding ER‐resident proteins, including some involved in unfolded protein response and others that affect glycosylation. Interestingly, we show that FAM46C expression is induced during plasma cell (PC) differentiation and that Ig mRNAs encoding heavy and light chains are 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 up‐regulates metastasis‐associated lncRNA MALAT1 and results in a sharp increase in the migration ability. This phenotype depends mainly on the activation of PI3K/Rac1 signalling, which might 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 suggest that its role as a tumour suppressor might be related to the inhibition of myeloma cell migration.

Genetic Abnormalities in Multiple Myeloma: Prognostic and Therapeutic Implications

“…Loss of FAM46C is associated in MM cell lines with an increase of cell migration mediated by the activation of the PI3K/Rac1 pathway, so it is reasonable to speculate that patients with del(1p12) or FAM46C mutations could benefit from PI3K and Rac1 inhibitors [ 106 ].…”

“…Both belong to the RNA processing pathway, which is responsible for regulating gene expression depending on specific environmental conditions. Even though FAM46C acts as a tumor-suppressor gene in MM [ 106 , 176 ], no prognostic impact has yet been demonstrated [ 105 ]. On the other hand, DIS3 mutations have recently been described as associated with a deleterious effect on the outcomes of patients treated with intensive therapy [ 174 ].…”

Mitochondrial Bioenergetics at the Onset of Drug Resistance in Hematological Malignancies: An Overview

“…There is no a unique driver genetic event in MM onset, but a complex variety of chromosomal and genomic rearrangements ( 125 ), occurring at different timepoints in response to external driving forces (e.g., exposure to microbes, chronic antigen stimulation, oxidative stress). Among the most frequent mutated genes, FAM46C has been involved in both mitochondrial and bioenergetics dysfunction associated to drug resistance ( 126 ), proteostasis ( 127 ), and disease onset.…”

Structural and functional characterization of multiple myeloma associated cytoplasmic poly(A) polymerase FAM46C

“…Recently, FAM46C has been characterized as a non‐canonical poly(A) polymerase (PAP) that functions as a tumor suppressor against B‐lymphocyte lineage originated MM [ 26 ]. In an human myeloma cell line model, knockout of FAM46C up‐regulates oncogenic long noncoding RNA (lncRNA) MALAT1 and promotes cell migration in a phosphatidylinositol 3‐kinase (PI3K)‐dependent manner [ 27 ]. During plasma cell differentiation, FAM46C is up‐regulated and directly controls antibody production [ 27 , 28 ].…”