Identification of mitochondrial RNA polymerase as a potential therapeutic target of osteosarcoma

Qi-Cai Han,Yun-Rong Zhu,Xiang-Yang Zhang,Fei-Fei Liu,Qing Tian,Song-Feng Chen,Peng-Hui Yan

doi:10.1038/s41420-021-00780-x

Abstract

POLRMT (RNA polymerase mitochondrial) is essential for transcription of mitochondrial genome encoding components of oxidative phosphorylation process. The current study tested POLRMT expression and its potential function in osteosarcoma (OS). The Cancer Genome Atlas (TCGA) cohorts and Gene Expression Profiling Interactive Analysis (GEPIA) database both show that POLRMT transcripts are elevated in OS tissues. In addition, POLRMT mRNA and protein levels were upregulated in local OS tissues as well as in established and primary human OS cells. In different OS cells, shRNA-induced stable knockdown of POLRMT decreased cell viability, proliferation, migration, and invasion, whiling inducing apoptosis activation. CRISPR/Cas9-induced POLRMT knockout induced potent anti-OS cell activity as well. Conversely, in primary OS cells ectopic POLRMT overexpression accelerated cell proliferation and migration. In vivo, intratumoral injection of adeno-associated virus-packed POLRMT shRNA potently inhibited U2OS xenograft growth in nude mice. Importantly, levels of mitochondrial DNA, mitochondrial transcripts and expression of respiratory chain complex subunits were significantly decreased in U2OS xenografts with POLRMT shRNA virus injection. Together, POLRMT is overexpressed in human OS, promoting cell growth in vitro and in vivo. POLRMT could be a novel therapeutic target for OS.

Highlights

Osteosarcoma (OS) is the most common bone malignancy among children and adolescents [1]
In the present study we showed that polymerase mitochondrial (POLRMT) is overexpressed in human OS, promoting OS cell growth in vitro and in vivo
Cells were significantly higher than those in the primary human osteoblasts (“Ob”) (Fig. 1F, G). These results show that POLRMT is overexpressed in human OS tissues and different human OS cells

Summary

INTRODUCTION

Osteosarcoma (OS) is the most common bone malignancy among children and adolescents [1]. OS comprises 2.4% of all malignancies in pediatric patients [2,3,4]. It arises from the primitive transformed cells of mesenchymal origin [5, 6]. Bonekamp et al, have recently developed the first-in-class specific POLRMT inhibitors to block mitochondrial transcription [18]. These POLRMT inhibitors potently suppressed cancer cell growth in mice [18]. In the present study we showed that POLRMT is overexpressed in human OS, promoting OS cell growth in vitro and in vivo

RESULTS

DISCUSSION

ETHICS APPROVAL