JUND Promotes Tumorigenesis via Specifically Binding on Enhancers of Multiple Oncogenes in Cervical Cancer

Abstract

Purpose

Enhancers are genomic regulatory elements located distally from the target gene, which play a critical role in determining cell identity and function. Dysregulation of enhancers has been frequently observed in various types of cancer, including cervical cancer. However, the identity of enhancers and their associated transcriptional regulators that are involved in cervical cancer remains unclear.

Methods

With bioinformatics and 3D genomics, we revealed the enhancers in cervical cancer cell line and calculated which transcription factor (TF) is specifically binding on them based on TFs motif database. We knockdowned this TF and studied its function in cervical cancer cell line in vivo and in vitro.

Results

We found 14,826 activated enhancers and predicted that JUND (JunD Proto-Oncogene) is relatively enriched in the sequences of these enhancers. Well-known oncogene MYC and JUN were regulated by JUND through enhancers. To further explore the roles of JUND in cervical cancer, we analyzed the gene expression data of clinical cervical cancer samples and knock-downed JUND by CRISPR-Cas9 in Hela cell line. We found JUND is over-expressed in cervical cancer and the expression of JUND increased along with the cervical cancer progresses. Knockdown of JUND decreased the proliferation of Hela cells in vitro and in vivo and blocked cell cycle in G1-phase. Transcriptome sequencing analysis revealed the identification of 2,231 differentially expressed genes in response to the JUND knockdown treatment. This perturbation resulted in the modulation of several biological processes and pathways that have been previously linked to cancer.

Conclusion

These findings provide evidence for the significant involvement of JUND in cervical cancer pathogenesis, thereby positioning JUND as a potential therapeutic target for the treatment of this disease.

Keywords:

• cervical cancer
• JUND
• transcription factor
• enhancer

Data Sharing Statement

The data used to support the findings of this study are available from the corresponding author upon reasonable request.

Ethics Approval Statement

The animal experiments were approved by the Institutional Animal Care and Use Committee, with the principles of the 3Rs (Replacement, Reduction and Refinement).

Disclosure

The authors declare that they have no competing interests.

Additional information

Funding

This study is supported by the National Natural Science Foundation of China (Grant No. 82260784).