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The GR-LEDGF/p75-HSP27 Axis Contributes to Cross-Resistance Between Enzalutamide and Docetaxel in Prostate Cancer
Pedro T Ochoa1, Evelyn S Sanchez-Hernandez1, Alfonso M Duran1,2
1Center for Health Disparities and Molecular Medicine, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA.
Abstract:
An emerging challenge in prostate cancer (PCa) treatment is the development of drug cross-resistance, wherein resistance to enzalutamide (ENZ), an androgen receptor signaling inhibitor (ARSI), also confers resistance to subsequent ARSI and docetaxel (DTX) treatments. The mechanisms underlying this drug cross-resistance remain unclear. Through RNA sequencing, we identified 93 overlapping differentially expressed genes (DEGs) in ENZ- and DTX-resistant PCa cells. Among the DEGs, HSPB1, which encodes heat shock protein 27 (HSP27), emerged as a key gene of interest. HSP27 is a known target of lens epithelium-derived growth factor p75 (LEDGF/p75), a transcription coactivator regulated by glucocorticoid receptor (GR). Both GR and LEDGF/p75 are overexpressed in advanced PCa and promote drug resistance. HSP27 was overexpressed in ENZ and DTX cross-resistant PCa cell lines and its expression was decreased upon GR or LEDGF/p75 silencing. ChIP sequencing confirmed GR binding at the HSPB1 promoter. Pharmacological targeting of HSP27 in drug-resistant cells reduced proliferation, clonogenicity, and tumorsphere formation, and restored sensitivity to ENZ and DTX. Notably, high transcript expression of a GR-LEDGF/p75-HSP27 gene panel correlated with worse overall survival in PCa patients (n = 4259). These findings identified this axis as a driver of PCa drug cross-resistance and promising therapeutic target for overcoming treatment failure.
Insights
Drug cross-resistance in prostate cancer (PCa) is a major challenge. Targeting the glucocorticoid receptor (GR)-LEDGF/p75-HSP27 pathway can overcome resistance to enzalutamide and docetaxel treatments.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Prostate cancer (PCa) treatment faces challenges with drug cross-resistance, where resistance to enzalutamide (ENZ) also leads to resistance against other androgen receptor signaling inhibitors (ARSIs) and docetaxel (DTX).
- The molecular mechanisms driving this cross-resistance are not fully understood, hindering the development of effective therapeutic strategies.
Purpose of the Study:
- To elucidate the mechanisms of drug cross-resistance in prostate cancer.
- To identify key molecular players and potential therapeutic targets for overcoming resistance to ARSI and DTX treatments.
Main Methods:
- RNA sequencing was employed to identify differentially expressed genes (DEGs) in enzalutamide- and docetaxel-resistant PCa cells.
- Chromatin immunoprecipitation sequencing (ChIP-seq) was used to confirm gene promoter binding.
- Functional assays assessed the impact of targeting heat shock protein 27 (HSP27) on cell proliferation, clonogenicity, and drug sensitivity.
Main Results:
- 93 overlapping DEGs were identified, with HSPB1 (encoding HSP27) highlighted as a key gene.
- HSP27 expression was elevated in resistant cells and linked to the overexpression of glucocorticoid receptor (GR) and lens epithelium-derived growth factor p75 (LEDGF/p75).
- Targeting HSP27 pharmacologically reduced tumor cell growth and restored sensitivity to ENZ and DTX, while a GR-LEDGF/p75-HSP27 gene signature correlated with poorer patient survival.
Conclusions:
- The GR-LEDGF/p75-HSP27 axis is identified as a critical driver of drug cross-resistance in prostate cancer.
- Targeting HSP27 presents a promising therapeutic strategy to overcome treatment failure in advanced PCa.
- This axis represents a potential biomarker for predicting patient outcomes.
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