ARID4B Promotes Lung Adenocarcinoma Malignancy by Activating GPRC5C transcription via Histone H1 Displacement

Guangnan Huang¹, Lei Gao^2,3, Shu Fang³, Likun Xu¹, Xiaowei Zhao⁴

¹Department of Respiratory and Critical Care Medicine, People’s Hospital of Xinjiang Uygur Autonomous Region Bainiaohu Hospital (The Second Affiliated Hospital of Xi’an Jiaotong University Xinjiang Hospital), Urumqi, China
²Department of Endocrinology and Metabolic Diseases, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
³Department of General Medicine, People’s Hospital of Xinjiang Uygur Autonomous Region Bainiaohu Hospital (The Second Affiliated Hospital of Xi’an Jiaotong University Xinjiang Hospital), Urumqi, China
⁴Hospital Office, People’s Hospital of Xinjiang Uygur Autonomous Region Bainiaohu Hospital (The Second Affiliated Hospital of Xi’an Jiaotong University Xinjiang Hospital), Urumqi, China

DOI : 10.4274/balkanmedj.galenos.2026.2025-10-260

Abstract

Background: Epithelial–mesenchymal transition (EMT) and cancer cell stemness (CSC) are critical processes that driving the invasion and lethality of lung adenocarcinoma (LUAD). The chromatin remodeler ARID4B has been implicated in other cancers; however, its specific role and underlying mechanism in LUAD progression remain unclear.

Aims: This study aimed to elucidate the function of ARID4B in LUAD.

Study Design: This study integrated bioinformatics analysis, in vitro cellular functional assays, and in vivo orthotopic lung cancer models to investigate the oncogenic role of ARID4B.

Methods: ARID4B expression and its correlation with patient prognosis were analyzed using public databases. ARID4B was silenced using two independent short hairpin RNAs in A549 and H1650 LUAD cell lines, and subsequent changes in invasion, migration, and stemness markers were assessed. Tumor metastasis was evaluated using orthotopic and tail-vein injection mouse models. The regulatory mechanism by which ARID4B controls GPRC5C expression was investigated using dual-luciferase reporter and chromatin immunoprecipitation assays.

Results: ARID4B was significantly upregulated in LUAD and was associated with poor patient prognosis. Silencing ARID4B in LUAD cells significantly reduced their invasion and migration capabilities (adj. p < 0.01). Furthermore, ARID4B knockdown resulted in downregulation of SNAIL, upregulation of E-cadherin, and impairment of stem-like characteristics, as demonstrated by decreased CSC marker expression and reduced sphere-forming ability (adj. p < 0.05). In the orthotopic model, ARID4B deficiency markedly inhibited tumor metastasis (adj. p < 0.001). Mechanistically, ARID4B transcriptionally activated GPRC5C (adj. p < 0.01). Furthermore, ARID4B knockdown increased histone H1 occupancy at the GPRC5C promoter (adj. p < 0.01), indicating that ARID4B facilitates an open chromatin state. Rescue experiments further confirmed that GPRC5C is required for ARID4B-mediated maintenance of tumor invasiveness and cancer stemness.

Conclusion: ARID4B promotes LUAD malignancy by transcriptionally activating GPRC5C, thereby driving EMT and cancer stemness.