HMGB1 promotes chemoresistance in small cell lung cancer by inducing PARP1-related nucleophagy

Weitao Shen; Qiong Lyu; Ruibin Yi; Yueqin Sun; Wei Zhang; Ting Wei; Yueming Zhang; Jian Shi; Jian Zhang

doi:10.1016/j.jare.2023.12.020

HMGB1 promotes chemoresistance in small cell lung cancer by inducing PARP1-related nucleophagy

J Adv Res. 2023 Dec 29:S2090-1232(23)00407-1. doi: 10.1016/j.jare.2023.12.020. Online ahead of print.

Authors

Weitao Shen¹, Qiong Lyu², Ruibin Yi¹, Yueqin Sun¹, Wei Zhang¹, Ting Wei¹, Yueming Zhang¹, Jian Shi³, Jian Zhang⁴

Affiliations

¹ Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, People's Republic of China.
² Department of Pathology, School of Basic Medical Science, Southern Medical University, Guangzhou, Guangdong, People's Republic of China.
³ Department of Pathology, School of Basic Medical Science, Southern Medical University, Guangzhou, Guangdong, People's Republic of China. Electronic address: jianshismu@126.com.
⁴ Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, People's Republic of China. Electronic address: zhangjian@i.smu.edu.cn.

PMID: 38159843
DOI: 10.1016/j.jare.2023.12.020

Abstract

Introduction: Small cell lung cancer (SCLC) is prone to chemoresistance, which is closely related to genome homeostasis-related processes, such as DNA damage and repair. Nucleophagy is the elimination of specific nuclear substances by cells themselves and is responsible for maintaining genome and chromosome stability. However, the roles of nucleophagy in tumour chemoresistance have not been investigated.

Objectives: The aim of this work was to elucidate the mechanism of chemoresistance in SCLC and reverse this chemoresistance.

Methods: RNA-seq data from SCLC cohorts, chemosensitive SCLC cells and the corresponding chemoresistant cells were used to discover genes associated with chemoresistance and patient prognosis. In vitro and in vivo experiments were performed to verify the effect of high-mobility group box 1 (HMGB1) knockdown or overexpression on the chemotherapeutic response in SCLC. The regulatory effect of HMGB1 on nucleophagy was then investigated by coimmunoprecipitation (co-IP) and mass spectrometry (MS), and the underlying mechanism was explored using pharmacological inhibitors and mutant proteins.

Results: HMGB1 is a factor indicating poor prognosis and promotes chemoresistance in SCLC. Mechanistically, HMGB1 significantly increases PARP1-LC3 binding to promote nucleophagy via PARP1 PARylation, which leads to PARP1 turnover from DNA lesions and chemoresistance. Furthermore, chemoresistance in SCLC can be attenuated by blockade of the PARP1-LC3 interaction or PARP1 inhibitor (PARPi) treatment.

Conclusions: HMGB1 can induce PARP1 self-modification, which promotes the interaction of PARP1 with LC3 to promote nucleophagy and thus chemoresistance in SCLC. HMGB1 could be a predictive biomarker for the PARPi response in patients with SCLC. Combining chemotherapy with PARPi treatment is an effective therapeutic strategy for overcoming SCLC chemoresistance.

Keywords: High-mobility group box protein B1 (HMGB1); Nucleophagy; PARP inhibitors; PARP1; Small cell lung cancer.