Curcuphenol possesses an unusual histone deacetylase enhancing activity that counters immune escape in metastatic tumours

Samantha L S Ellis; Sarah Dada; Lilian L Nohara; Iryna Saranchova; Lonna Munro; Cheryl G Pfeifer; Brett A Eyford; Tunc Morova; David E Williams; Ping Cheng; Nathan A Lack; Raymond J Andersen; Wilfred A Jefferies

doi:10.3389/fphar.2023.1119620

Curcuphenol possesses an unusual histone deacetylase enhancing activity that counters immune escape in metastatic tumours

Front Pharmacol. 2023 Aug 10:14:1119620. doi: 10.3389/fphar.2023.1119620. eCollection 2023.

Authors

Samantha L S Ellis^{1

2

3

4}, Sarah Dada^{1

2

3

4

5

6}, Lilian L Nohara^{1

2

3}, Iryna Saranchova^{1

2

3

4

5

6}, Lonna Munro^{1

2

3

5}, Cheryl G Pfeifer^{1

2

3

5}, Brett A Eyford^{1

2

3}, Tunc Morova⁵, David E Williams⁷, Ping Cheng⁷, Nathan A Lack^{5

8}, Raymond J Andersen⁷, Wilfred A Jefferies^{1

2

3

4

5

6}

Affiliations

¹ Michael Smith Laboratories, University of British Columbia, Vancouver, BC, Canada.
² Centre for Blood Research, University of British Columbia, Vancouver, BC, Canada.
³ The Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC, Canada.
⁴ Department of Microbiology and Immunology, University of British Columbia, Vancouver, BC, Canada.
⁵ Vancouver Prostate Centre, Vancouver Coastal Health Research Institute, Vancouver, BC, Canada.
⁶ Departments of Medical Genetics, Zoology, and Urologic Sciences, University of British Columbia, Vancouver, BC, Canada.
⁷ Departments of Chemistry and Earth Ocean, and Atmospheric Sciences, University of British Columbia, Vancouver, BC, Canada.
⁸ School of Medicine, Koç University, Istanbul, Türkiye.

Abstract

Curcuphenol, a common component of the culinary spices, naturally found in marine invertebrates and plants, has been identified as a novel candidate for reversing immune escape by restoring expression of the antigen presentation machinery (APM) in invasive cancers, thereby resurrecting the immune recognition of metastatic tumours. Two synthetic curcuphenol analogues, were prepared by informed design that demonstrated consistent induction of APM expression in metastatic prostate and lung carcinoma cells. Both analogues were subsequently found to possess a previously undescribed histone deacetylase (HDAC)-enhancing activity. Remarkably, the H3K27ac ChIPseq analysis of curcuphenol-treated cells reveals that the induced epigenomic marks closely resemble the changes in genome-wide pattern observed with interferon-γ, a cytokine instrumental for orchestrating innate and adaptive immunity. These observations link dietary components to modifying epigenetic programs that modulate gene expression guiding poised immunity.

Keywords: HDAC; antigen processing machinery; curcuphenol; drug discovery; epigenetic modification; histone deacetylase activity; major histocompatibility complex class I; tumours.

Grants and funding

This work was supported by an Industrial Partnered Collaborative Research grant from the Canadian Institutes of Health Research (CIHR; MOP-102698), in partnership with Pascal Biosciences, Inc. to WAJ; a grant from the Natural Sciences and Engineering Research Council (NSERC; RGPIN 869-13) to RJA; and TM was funded through a NSERC Bioinformatics CREATE Program co-hosted at the University of British Columbia and Simon Fraser University.