Advancements and challenges of R-loops in cancers: Biological insights and future directions

Dengxiong Li; Fanglin Shao; Xinrui Li; Qingxin Yu; Ruicheng Wu; Jie Wang; Zhipeng Wang; Dilinaer Wusiman; Luxia Ye; Yiqing Guo; Zhouting Tuo; Wuran Wei; Koo Han Yoo; William C Cho; Dechao Feng

doi:10.1016/j.canlet.2024.217359

Advancements and challenges of R-loops in cancers: Biological insights and future directions

Cancer Lett. 2025 Feb 1:610:217359. doi: 10.1016/j.canlet.2024.217359. Epub 2024 Nov 27.

Authors

Dengxiong Li¹, Fanglin Shao², Xinrui Li², Qingxin Yu³, Ruicheng Wu¹, Jie Wang¹, Zhipeng Wang⁴, Dilinaer Wusiman⁵, Luxia Ye⁶, Yiqing Guo⁶, Zhouting Tuo⁷, Wuran Wei¹, Koo Han Yoo⁸, William C Cho⁹, Dechao Feng¹⁰

Affiliations

¹ Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, 610041, China.
² Department of Rehabilitation, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, China.
³ Department of Pathology, Ningbo Clinical Pathology Diagnosis Center, Ningbo City, Zhejiang Province, 315211, China.
⁴ Department of Urology, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China.
⁵ Department of Comparative Pathobiology, College of Veterinary Medicine, Purdue University, West Lafayette, IN, 47907, USA; Purdue Institute for Cancer Research, Purdue University, West Lafayette, IN, USA.
⁶ Department of Public Research Platform, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, China.
⁷ Department of Urological Surgery, Daping Hospital, Army Medical Center of PLA, Army Medical University, Chongqing, China.
⁸ Department of Urology, Kyung Hee University, South Korea. Electronic address: [email protected].
⁹ Department of Clinical Oncology, Queen Elizabeth Hospital, Hong Kong Special Administrative Region of China. Electronic address: [email protected].
¹⁰ Division of Surgery & Interventional Science, University College London, London, W1W 7TS, UK. Electronic address: [email protected].

PMID: 39613219
DOI: 10.1016/j.canlet.2024.217359

Abstract

R-loops involve in various biological processes under human normal physiological conditions. Disruption of R-loops can lead to disease onset and affect the progression of illnesses, particularly in cancers. Herein, we summarized and discussed the regulative networks, phenotypes and future directions of R-loops in cancers. In this review, we highlighted the following insights: (1) R-loops significantly influence cancer development, progression and treatment efficiency by regulating key genes, such as PARPs, BRCA1/2, sex hormone receptors, DHX9, and TOP1. (2) Currently, the ATM, ATR, cGAS/STING, and noncanonical pathways are the main pathways that involve in the regulatory network of R-loops in cancer. (3) Cancer biology can be modulated by R-loops-regulated phenotypes, including RNA methylation, DNA and histone methylation, oxidative stress, immune and inflammation regulation, and senescence. (4) Regulation of R-loops induces kinds of drug resistance in various cancers, suggesting that targeting R-loops maybe a promising way to overcome treatment resistance. (5) The role of R-loops in tumorigenesis remains controversial, and senescence may be a crucial research direction to unravel the mechanism of R-loop-induced tumorigenesis. Looking forward, further studies are needed to elucidate the specific mechanisms of R-loops in cancer, laying the groundwork for preclinical and clinical research.

Keywords: Cellular senescence; Drug resistance; Methylation; R-loops; Tumor immunity.

Publication types

Review

MeSH terms

Animals
Carcinogenesis / genetics
Drug Resistance, Neoplasm / genetics
Gene Expression Regulation, Neoplastic
Humans
Neoplasms* / genetics
Neoplasms* / pathology
Neoplasms* / therapy
R-Loop Structures*
Signal Transduction