Post-transcriptional regulation of BIRC5/survivin expression and induction of apoptosis in breast cancer cells by tristetraprolin

ABSTRACT

Inhibition of apoptosis is one of the hallmarks of cancer and is a target of various therapeutic interventions. BIRC5 is an inhibitor of apoptosis that is aberrantly expressed in cancer leading to sustained growth of tumours. Post-transcriptional control mechanisms involving RNA-binding proteins and AU-rich elements (AREs) are fundamental to many cellular processes and changes in the expression or function of these proteins can promote an aberrant and pathological phenotype. BIRC5 mRNA has an ARE in its 3’ UTR making it a candidate for regulation by the RNA binding proteins tristetraprolin (TTP) and HuR (ELAVL1). In this study, we investigated the binding of TTP and HuR by RNA-immunoprecipitation assays and found that these proteins were associated with BIRC5 mRNA to varying extents. Consequently, BIRC5 expression decreased when TTP was overexpressed and apoptosis was induced. In the absence of TTP, BIRC5 mRNA was stabilized, protein expression increased and the number of apoptotic cells declined. As an ARE-mRNA stabilizing protein, recombinant HuR led to upregulation of BIRC5 expression, whereas HuR silencing was concomitant with downregulation of BIRC5 mRNA and protein and increased cell death. Survival analyses demonstrated that increased TTP and low BIRC5 expression predicted an overall better prognosis compared to dysregulated TTP and high BIRC5. Thus, the results present a novel target of ARE-mediated post-transcriptional regulation.

KEYWORDS:

• Apoptosis
• BIRC5
• post-transcriptional regulation
• RNA-binding protein
• tristetraprolin

Acknowledgments

The authors would like to thank Mr Pulicat Manogaran and Mr Amer Almazrou for their assistance with flow cytometry.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Author contributions

Khalid S.A. Khabar: conceptualization, reviewing and editing final draft. Norah Al-Souhibani: conceptualization, methodology, validation, original draft writing and editing, formal analysis, supervision and project administration. Suhad Al-Yahya, Walid Moghrabi, Maher Al-Saif and Maha Al-Ghamdi: investigation, validation, formal analysis, resources, editing and reviewing final draft.

Data availability statement

Data sharing is not applicable to this article as no datasets were generated or analysed during the current study.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/15476286.2023.2286101

Additional information

Funding

Intramural funding from King Faisal Specialist Hospital and Research Center (RAC # 2150004) supported this work.