The Rpd3/Hda1 family of histone deacetylases regulates azole resistance in Candida albicans
Abstract
Objectives: The histone deacetylase (HDAC) has recently been linked to the morphogenesis and virulence of yeast. However, the effects of HDAC on antifungal susceptibility are not well understood. We sought to characterize the action of histone deacetylation on azole resistance in Candida albicans and its possible mechanism of action. Methods: A total of 40 C. albicans strains were studied. Azole susceptibility with or without trichostatin A (TSA) was determined according to the CLSI microdilution method. The null mutants of HDA1 and RPD3 (genes targeted by TSA) were also investigated using drop-plate assays and a rapid acquisition of adaptation to the azole test. Transcriptional levels of HDAC genes and efflux genes were quantified using RT–PCR for both the basal and fluconazole-induced conditions. Results: The inhibition of HDACs by TSA (0.25 mg/L) markedly reduced the trailing growth and the growth of most C. albicans strains. Trailing growth for C. albicans strains was decreased from 2-fold to 256-fold at 48 h. The deletion of HDA1 or RPD3 increased the susceptibility to azoles compared with the WT strain. The expression of HDA1 and RPD3 was up-regulated to different levels, and returned to the level of the susceptible parental strain when stable resistance had formed during the course of acquired fluconazole resistance both in vitro and in vivo. Efflux genes were poorly expressed in mutant strains compared with those of the WT strain. Conclusions: Our results indicate the important role of the Rpd3/Hda1 family in the development of azole resistance in C. albicans. Histone deacetylation may govern the expression of genes related to the early stages of adaptation to azole stress, such as efflux pump genes.
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Over the past 20 years, these strains have been extensively investigated at the genomic and transcriptomic levels to elucidate the mechanisms of resistance, revealing a combination of various resistance mechanisms among the resistant strains.
“Over the past 20 years, these strains have been extensively investigated at the genomic and transcriptomic levels to elucidate the mechanisms of resistance (25–35), revealing a combination of various resistance mechanisms among the resistant strains (Table 1).”
From Potential role of lysine acetylation in the stepwise adaptation of <i>Candida albicans</i> to fluconazole (2025) · cites this paper as [34]
In fluconazole-resistant C. albicans isolates, expression of HDA1 and RPD3 is upregulated specifically in the early stages of resistance acquisition.
“For instance, the expression of lysine deacetylases HDA1 and RPD3 are upregulated in fluconazole-resistant C. albicans isolates, specifically in the early stages of resistance acquisition90.”
From Molecular mechanisms governing antifungal drug resistance (2023) · cites this paper as [90]
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Self-citation
- Authors
- Li, X., Cai, Q., Mei, H., Zhou, X., Shen, Y., Li, D., & Liu, W.
- Affiliations
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- Corresponding author
- Liu, Weida
- Venue
- Journal of Antimicrobial Chemotherapy
- Publisher
- Oxford University Press (OUP)
- Published
- 2015-03-29
- Volume
- 70
- Issue
- 7
- Pages
- 1993-2003
- ISSN
- 0305-7453 (ISSN-L)
- 1460-2091
- OpenAlex
- W2002877829
- Cited by
- 64
- References
- 48
- Citations by year
- 2026: 4 · 2025: 9 · 2024: 6 · 2023: 7 · 2022: 6 · 2021: 8 · 2020: 6 · 2019: 5 · 2018: 4 · 2016: 5 · 2015: 4
- FWCI
- 3.37
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Antimicrobial Chemotherapy (publishedVersion)
- PubMed (publishedVersion)
- HighWire Press Open Archive (submittedVersion)
- Funders
- University of Missouri
- Topics
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- Keywords
- histone deacetylase, Rpd3, Hda1, Candida albicans, azole resistance, fluconazole resistance, trichostatin A, histone deacetylation, efflux pump genes, acquired drug resistance, antifungal susceptibility, yeast morphogenesis
- MeSH terms
- Antifungal Agents, Azoles, Candida albicans, Histone Deacetylases, Humans, Microbial Sensitivity Tests, Gene Expression Regulation, Fungal, Gene Deletion, Gene Expression Profiling, Drug Resistance, Fungal, Real-Time Polymerase Chain Reaction
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