Identification and characterisation of IRX4 isoforms as novel targets in prostate cancer

Overview

Prostate cancer (PCa) is the second leading cause of cancer-related death in Australian men. There is no cure for advanced prostate cancer patients who develop resistance to currently available treatments. Alternative splicing (AS) is tightly regulated to maintain genomic stability in humans (Liyanage et al 2019). Aberrant RNA splicing of cancer-causing genes has been reported as a major cause of treatment escape in prostate cancer patients. Iroquois-class homeodomain protein 4 (IRX4) is a TALE homeobox transcription factor which has been implicated in prostate cancer (PCa) as a tumor suppressor through genome-wide association studies (GWAS) and functional follow-up studies.

We were able to identify twelve IRX4 transcripts encoding four IRX4 protein isoforms in prostate cancer cell lines (Fernando et al, 2021) and clinical specimens. They demonstrate unique expression profiles between androgen-responsive and nonresponsive cell lines. Some of these isoforms lack functional domains compared to full-length IRX4 protein isoform. We observed significant differences in cellular function between isoforms in prostate cancer cell lines. Currently, we are investigating their mechanism of action in prostate cancer aetiology and progression. These IRX4 isoforms may have distinct role in PCa hallmarks by regulating unique signalling pathways.

References

Liyanage, Fernando A, Batra J. (2019). Cancer Metastasis Review, 38(3):389-415.

Fernando, A., Liyanage, C., Moradi, A., Janaththani, P., & Batra, J. (2021). Genes, 12(5).

Research activities

This project may employ in vitro prostate cancer cell line-based techniques such as:

• qPCR
• RT-PCR
• western blot
• cell culture
• cell proliferation assay
• cell migration and invasion assay by incucyte
• plasmid isolation
• RNA isolation
• co-immunoprecipitation
• chip sequencing.

Outcomes

The project aims to:

• investigate the functional role of IRX4 isoforms in prostate cancer in vitro
• investigate the mechanism of action of IRX4 isoforms in prostate cancer pathogenesis
• validate of IRX4 transcript variant and isoform expression in patient samples and to determine their diagnostic and prognostic significance in prostate cancer.

Our study will thus provide novel insights into mechanisms underlying PCa tumour progression and therapeutic resistance and will help to identify novel diagnostic biomarkers and potential therapeutic targets.

Skills and experience

Experience in mammalian cell culture is beneficial but not necessary. However, you should have an interest to acquire these technical skills.

Knowledge of basic biochemistry, cell and molecular biology, and basic laboratory techniques will be an advantage.

Keywords

• prostate cancer
• alternative splicing
• androgen-response
• transcription factor
• protein isoforms

Contact

Contact the supervisor for more information.