MTH1 expression is required for effective transformation by oncogenic HRAS.

Maria G Giribaldi,Katherine Halvorsen,Priyamvada Rai,Anisleidys Munoz,Asmita Patel

doi:10.18632/oncotarget.3447

Maria G Giribaldi, Katherine Halvorsen + Show 3 more

Open Access

https://doi.org/10.18632/oncotarget.3447

Copy DOI

Abstract

Due to sustaining elevated reactive oxygen species (ROS), oncogenic RAS-transformed cells upregulate redox-protective genes, among them the mammalian 8-oxodGTPase, MutT Homolog 1 (MTH1). We previously showed MTH1 abrogates RAS oncogene-induced senescence (OIS) in normal cells and that its inhibition compromises the tumorigenicity of established oncogenic RAS-harboring cancer cells. Here, we investigated how pre-transformation MTH1 levels in immortalized cells influence HRASV12-induced oncogenic transformation. We find MTH1 suppression prior to HRASV12 transduction into BEAS2B immortalized epithelial cells compromised maintenance of high RASV12- and oncogenic ROS-expressing cell populations. Furthermore, pre-transformation MTH1 levels modulated the efficiency of HRASV12-mediated soft agar colony formation. Downstream transformation-associated traits such as the epithelial-mesenchymal transition (EMT) were also compromised by MTH1 inhibition. These collective effects were observed to a greater degree in cells harboring high vs. low RASV12 levels, suggesting MTH1 is required for tumor cells to accumulate RAS oncoprotein. This is significant as, a priori, one cannot ascertain whether tumor-promoting adaptations wrought by introducing oncogenic RAS into an immortalized cell are capable of overcoming pre-transformation deficiencies. Our results suggest nucleotide pool sanitization comprises an important transformation-promoting requirement that, if compromised, cannot be adequately compensated post-transformation and thus is likely to affect optimal development and progression of RAS-driven tumors.

Highlights

30% of all human malignancies sustain activating RAS mutations, which engender aggressive, treatment-resistant tumors
We have previously shown that MutT Homolog 1 (MTH1) is elevated in HRASV12-transformed breast cancer cells relative www.impactjournals.com/oncotarget to their non-transformed counterparts and that MTH1 overexpression enables normal cells to overcome oncogene-induced senescence (OIS), the first barrier to oncogenic transformation [9]
Our studies show that elevated MTH1 levels enhance RASV12induced soft agar colony formation and that MTH1 inhibition reduces transformation efficiency and inhibits maintenance of oncogene-induced epithelial-mesenchymal transition (EMT) as well as glycolytic adaptation

Summary

Introduction

30% of all human malignancies sustain activating RAS mutations, which engender aggressive, treatment-resistant tumors. We note that the extent of MTH1 suppression-associated molecular changes in EMT markers is less fully correlative with the levels of RAS oncoprotein than either the morphological or motility changes. This may reflect a greater functional requirement for the full complement of EMT-associated molecular factors in high RASV12-expressing cells relative to low RASV12-expressing cells, possibly due greater oncogenic dependence in the high RAS cells [22, 23]

Methods

Results

Conclusion