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ORAI1-Regulated Gene Expression in Breast Cancer Cells: Roles for STIM1 Binding, Calcium Influx and Transcription
Mélanie Robitaille1, Shao Ming Chan1, Amelia A Peters1
1School of Pharmacy, The University of Queensland, Brisbane, QLD 4102, Australia.
International Journal of Molecular Sciences
|June 10, 2022
Summary
Store-operated calcium entry (SOCE) protein ORAI1 regulates gene transcription in basal breast cancer cells. ORAI1 influences cancer progression by controlling gene expression, impacting breast cancer development.
Area of Science:
- Cellular Biology
- Molecular Oncology
- Calcium Signaling
Background:
- Calcium homeostasis is altered in breast cancers, with store-operated calcium entry (SOCE) playing a key role.
- ORAI1, a critical component of SOCE, is upregulated in basal breast cancer cells.
- The specific role of ORAI1 in regulating gene transcription in this subtype remains largely unknown.
Purpose of the Study:
- To investigate the function of ORAI1 in gene transcriptional regulation in basal breast cancer cells.
- To determine if ORAI1's role in transcription is dependent on its pore function and interaction with STIM1.
- To elucidate ORAI1's contribution to breast cancer progression via gene expression modulation.
Main Methods:
- CRISPR-Cas9 gene editing was employed to disrupt ORAI1 expression in MDA-MB-231 and MDA-MB-468 basal breast cancer cell lines.
- ORAI1 wild-type and mutant variants were reintroduced into knockout cells to assess functional roles.
- Transcriptional changes were analyzed in response to ORAI1 manipulation and SOCE activation.
Main Results:
- In MDA-MB-231 cells, ORAI1 regulated *PTGS2* transcription independently of calcium store depletion, contingent on ORAI1 pore function and STIM1 binding.
- In MDA-MB-468 cells, SOCE activation led to ORAI1-dependent increases in *IL6* transcription, also requiring ORAI1 pore function and STIM1 binding.
- ORAI1-mediated *IL6* transcriptional changes were associated with NFAT1 translocation.
Conclusions:
- ORAI1 plays a significant role in regulating gene transcription (*PTGS2* and *IL6*) in basal breast cancer cells.
- This transcriptional regulation is dependent on ORAI1's pore activity and STIM1 interaction.
- The findings suggest ORAI1 contributes to breast cancer progression through modulation of gene expression, highlighting its potential as a therapeutic target.
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