REV1 promotes lung tumorigenesis by activating the Rad18/SERTAD2 axis

Yunshang Chen,Tao Zhang,Biyuan Xing,Dong Zhou,Kunyu Yang,Gang Wu,Xijie Yang,Zilong Wu,Zhenyu Li,Xiaorong Dong,Xinrui Rao,Yingzhuo Xu,Xiaohua Jie

doi:10.1038/s41419-022-04567-5

Abstract

REV1 is the central member of the family of TLS polymerases, which participate in various DNA damage repair and tolerance pathways and play a significant role in maintaining genomic stability. However, the role of REV1 in tumors is rarely reported. In this study, we found that the expression of REV1 was significantly upregulated in lung cancer tissues compared with matched adjacent tissues and was associated with poor prognosis. Functional experiments demonstrated that REV1 silencing decreased the growth and proliferation capacity of lung cancer cells. Mechanistically, REV1 upregulated the expression of SERTAD2 in a Rad18-dependent manner, thereby promoting lung carcinogenesis. A novel REV1 inhibitor, JH-RE-06, suppressed lung tumorigenesis in vivo and in vitro and was shown to be safe and well tolerated. Our study confirmed that REV1 is a potential diagnostic marker and therapeutic target for lung cancer and that JH-RE-06 may be a safe and efficient therapeutic agent for NSCLC.

Highlights

Lung cancer has one of the highest incidences worldwide and is the leading cause of tumor-related death [1, 2]
Through IHC staining of a lung adenocarcinoma tissue microarray containing 77 pairs of cancerous and paracancerous tissues, we found that the expression of REV1 in lung cancer tissue
We demonstrated that REV1 upregulates the expression of the transcriptional coregulator SERTAD2 in a Rad18-dependent manner, which in turn facilitates lung tumorigenesis

Summary

Introduction

Lung cancer has one of the highest incidences worldwide and is the leading cause of tumor-related death [1, 2]. New diagnosis and treatment methods continue to emerge, many challenges remain in improving the clinical outcomes of lung cancer patients [4]. It is urgent to better understand the mechanism of lung tumorigenesis and identify new therapeutic targets. As an important part of the DNA damage tolerance pathways, TLS protects tumor cells and allows them to overcome oncogene-induced replication stress (OIRS) during tumor progression [8, 9]. Taken together, these observations indicate that TLS is closely related to carcinogenesis and tumor progression

Methods

Results

Conclusion