Serine tRNAs (
tRNASer) are frequently overexpressed in
tumors and associated with poor prognosis and increased risk of recurrence in
breast cancer. Impairment of
tRNA biogenesis and abundance also impacts
proteome homeostasis, and activates
protein quality control systems. Herein, we aimed at testing whether increasing
tRNASer abundance could foster
tumor establishment through activation of the UPR. In order to do so, firstly we confirmed that the expression of tRNA-Ser-AGA-2-1 [hereafter
tRNASer(AGA)] was upregulated by 1.79-fold in Stage I NSCLC
tumors when compared to normal adjacent tissue. To study the impact of
tRNASer(AGA) in early stage
tumorigenesis, we induced its upregulation in a non-tumoral bronchial cell line, BEAS-2B. Upregulation of this
tRNA increased cellular proliferation and
protein synthesis rate, driven by eIF2α dephosphorylation and ATF4 activation downstream of PERK signaling. Futhermore,
tRNASer(AGA) enhanced transformation potential in vitro, and promoted the establishment of slow growing
tumors with aggressive features in nude mice. Our work highlights the importance of studying
tRNA deregulation on early stage
tumorigenesis, as they may be potential
malignancy and aggressiveness
biomarkers.