SIRT1 deacetylated and stabilized XRCC1 to promote chemoresistance in lung cancer

Neelum Aziz Yousafzai,Hongchuan Jin,Xian Wang,Qiyin Zhou,Wenxia Xu,Lifeng Feng,Vivian Yvonne Shin,Qiqi Shi,Hui Chen,Jinye Xu

doi:10.1038/s41419-019-1592-3

Abstract

Chemoresistance is one of the most important challenges in the clinical management of lung cancer. SIRT1 is a NAD dependent protein deacetylase and implicated in diverse cellular processes such as DNA damage repair, and cancer progression. SIRT1 is upregulated in chemoresistant lung cancer cells, genetic knockdown or chemical inhibition of SIRT1 reversed chemoresistance by enhancing DNA damage and apoptosis activation, accompanied with XRCC1 degradation. E3 ligase β-TrCP catalyzed the poly-ubiquitination of XRCC1 to promote its proteasome-dependent degradation. SIRT1 bound and deacetylated XRCC1 at lysine K260, K298 and K431, preventing it from β-TrCP-dependent ubiquitination. Mutations of these three lysine sites in XRCC1 abrogated the interaction with β-TrCP and prolonged the half-life of XRCC1 protein. Here, we describes SIRT1 confers chemoresistance to lung cancer cells by deacetylating and stabilizing XRCC1. Therefore, targeting SIRT1 might be a new strategy to manage the chemoresistance of lung cancer, and probably other cancers.

Highlights

Lung cancer is most death responsible disease in both men and women worldwide
H460 became more resistant to chemotherapeutic drug cisplatin significantly (Fig. 1c, IC50 increased from 2 μg/ ml to 6.3 μg/ml 72 h. after SIRT1 overexpression), accompanied with less apoptosis revealed by Annexin V/
(see figure on previous page) Fig. 4 SIRT1 upregulates X-ray crosscomplementing-1 (XRCC1) protein through inhibiting its degradation. a Protein expressions in H460-R cells before and after SIRT1 knockdown were analyzed by western blotting. b, c Protein expressions in H460-R cells before and after EX-527 (b) or NAM (c) treatment were analyzed by western blotting. d Protein expressions in H460 cells before and after SIRT1 overexpression were analyzed by western blotting. e, f XRCC1 protein levels in EX-527 (15 μM) (e) or NAM (2 mM) -treated (f)

Summary

Introduction

Treatment of lung cancer remains a big challenge, great developments such as EGFRTKI (tyrosine kinase inhibitor) based targeted therapy have been achieved[1]. Lung cancer cells are able to become resistant to many drugs due to genetic and epigenetic alterations[2]. Platinum-based chemotherapy is the most standard choice for the treatment of various solid cancers including lung cancer[3]. The mechanisms underlying resistance to platinum-based chemotherapy has been extensively explored to provide rational strategies for overcoming damage repair by activating multiple repair pathways like homologous recombination (HR), nucleotide excision repair (NER), base excision repair (BER) and nonhomologous end joining (NHEJ)[7], as all these pathways has been regulated by SIRT1 through deacetylation including Nijmegen breakage syndrome protein (NBS1),[8] Ku709 and apurinic/apyrimidinic endonuclease[10]. The function and relevance of SIRT1 to chemoresistance of lung cancer cells was largely unknown

Methods

Results

Conclusion