Gene Amplification-Associated Overexpression of the Selenoprotein tRNA Enzyme TRIT1 Confers Sensitivity to Arsenic Trioxide in Small-Cell Lung Cancer.

Laia Coll-Sanmartin,Alberto Bueno-Costa,Neus Ruiz-Xiviller,Alberto Villanueva,Takashi Kohno,Margalida Rosselló-Tortella,David Piñeyro,Manel Esteller,Annika Kotter,Reika Kawabata-Iwakawa,Veronica Davalos,Fernando Setien,Isabel Granada,Jun Yokota,Mark Helm

doi:10.3390/cancers13081869

Abstract

Simple SummarySmall-cell lung cancer accounts for approximately 13% of all new lung cancer diagnoses, but in contrast to non-small-cell lung cancer, the implementation of targeted treatments in small-cell lung cancer has been limited, with little improvement in the clinical outcome in the last several decades. Exploring new pathways for targeted therapy, we have observed that extra-copies of the tRNA modifier TRIT1, involved in the translation of selenoproteins, confers sensitivity to arsenic trioxide in small-cell lung cancer. This finding could open a new therapeutic niche for a tumor type with such a dismal clinical course.The alteration of RNA modification patterns is emerging as a common feature of human malignancies. If these changes affect key RNA molecules for mRNA translation, such as transfer RNA, they can have important consequences for cell transformation. TRIT1 is the enzyme responsible for the hypermodification of adenosine 37 in the anticodon region of human tRNAs containing serine and selenocysteine. Herein, we show that TRIT1 undergoes gene amplification-associated overexpression in cancer cell lines and primary samples of small-cell lung cancer. From growth and functional standpoints, the induced depletion of TRIT1 expression in amplified cells reduces their tumorigenic potential and downregulates the selenoprotein transcripts. We observed that TRIT1-amplified cells are sensitive to arsenic trioxide, a compound that regulates selenoproteins, whereas reduction of TRIT1 levels confers loss of sensitivity to the drug. Overall, our results indicate a role for TRIT1 as a small-cell lung cancer-relevant gene that, when undergoing gene amplification-associated activation, can be targeted with the differentiation agent arsenic trioxide.

Highlights

Altered RNA and protein patterns are a feature of human tumors
To find tumor-associated genetic and epigenetic changes in the A37-modifying enzymes TRIT1 and CDK5RAP1 (Figure 1A), we data-mined a collection of about 1000 human cancer cell lines in which the transcriptome, DNA methylation landscape, exome sequence, and gene copy number were available [22,23]
We observed that 82% (9 of 11) and 100% (11 of 11) of the TRIT1 amplified cell lines showed RB1 and TP53 mutations, respectively; an indistinguishable distribution to the one found in the non-amplified cell lines (Fisher’s exact test, p = 0.4781 and p = 1, respectively)

Summary

Introduction

Altered RNA and protein patterns are a feature of human tumors. These aberrant expression profiles may arise by myriad mechanisms. RNA molecules exhibit chemically modified nucleosides that together form the denominated epitranscriptome [1,2,3]. An emerging body of data in cancer biology indicates that significant changes occur in the epitranscriptome with the appearance of genetic and epigenetic defects in RNA-modifier genes [1,2,3]. RNA modifications are relevant in transfer RNA molecules (tRNAs). These affect protein translation function at several levels, including amino acid loading, wobbling or translation efficiency, and translational fidelity [4,5]. TRNA modifications and tRNA modifier enzymes are disrupted in a variety of human diseases, including cancer [6,7,8]

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