Histone ubiquitination-related gene CUL4B promotes lung adenocarcinoma progression and cisplatin resistance

Yanjun Yin; Lifeng Zhang; Yinchuan Zeng; Diang Chen; Haien Guan; Guoping Ran; Kangming Du

doi:10.3389/fgene.2023.1242137

Histone ubiquitination-related gene CUL4B promotes lung adenocarcinoma progression and cisplatin resistance

Front Genet. 2023 Nov 24:14:1242137. doi: 10.3389/fgene.2023.1242137. eCollection 2023.

Authors

Yanjun Yin^#¹, Lifeng Zhang^#², Yinchuan Zeng^#³, Diang Chen², Haien Guan⁴, Guoping Ran⁵, Kangming Du²

Affiliations

¹ Department of Emergency, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China.
² Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China.
³ The General Hospital of Western Theater Command, Chengdu, China.
⁴ Center of Stem Cell and Regenerative Medicine, The People's Hospital of Gaozhou, Gaozhou, China.
⁵ Chengdu Second People's Hospital, Chengdu, China.

^# Contributed equally.

Abstract

Background: The role of the histone ubiquitination-related gene in the cisplatin resistance of lung adenocarcinoma (LUAD) remains an intricate subject. Methods: We accessed transcriptome data of both wild type and cisplatin-resistant cells from the GSE108214 dataset, and garnered transcriptome and clinical data of LUAD patients from The Cancer Genome Atlas (TCGA) database. Utilizing the R software, we analyzed these public datasets in depth. Real-time Quantitative PCR (qPCR) was used to detect the RNA level of CUL4B. Effect of CUL4B on cell proliferation was evaluated using CCK8 and colony formation assay. Effect of CUL4B on cell invasion was evaluated using transwell assay. Cisplatin sensitivity was evaluated by calculating IC50. Results: Our analysis shed light on the significance of the histone ubiquitination-related gene, CUL4B, in relation to cisplatin resistance and the overall survival rates of LUAD patients. Notably, CUL4B was found to be overexpressed in both lung cancer tissues and cells. Meanwhile, in vitro experiments indicated can CUL4B significantly promote the proliferation, invasion and migration of lung cancer cells. Furthermore, suppressing CUL4B expression led to a noticeable reduction in the IC50 value of cisplatin in lung cancer cells. A deep dive into biological enrichment analysis revealed that among patients exhibiting high CUL4B expression, there was a pronounced activation of the G2M checkpoint and the PI3K/AKT/mTOR signaling pathways. Immune microenvironment analysis has revealed that patients with elevated CUL4B expression may exhibit increased infiltration of M2 macrophages, coupled with a reduced infiltration of CD8⁺ T cells and activated NK cells. Notably, we observed higher CUL4B expression among those who responded positively to immunotherapy. Conclusion: These findings underscore the significance of CUL4B in the resistance to cisplatin in lung cancer, highlighting its potential as a therapeutic target.

Keywords: CUL4B; cisplatin resistance; histone; lung cancer; ubiquitination.