Epigenetic Regulator in Double-Negative Prostate Cancer
Posted: Tuesday, August 6, 2019
The epigenetic regulator polycomb repressor complex 1 (PRC1) seems to mediate the immunosuppression, self-renewal, and aberrant neoangiogenesis that characterizes double-negative prostate cancer, according to Filippo G. Giancotti, MD, PhD, of The University of Texas MD Anderson Cancer Center, and colleagues. Their study results were published in Cancer Cell.
In this preclinical study, a series of mechanistic assays were used to probe the role of PRC1 in patient data sets, cell lines, and mouse models. Through genetic and small-molecule compound screens, the authors identified the cytokine CCL2 as the major target of, and GW-516, as an inhibitor of, PRC1.
Using patient data sets, the researchers found PRC1 components, RNF2 and BMI1, were upregulated in castration-resistant metastatic samples, but not in samples from organ-confined primary tumors. In vitro cells with elevated levels of PRC1 seemed to acquire mesenchymal traits. Depletion of RNF2 decreased CCL2, prevented bone metastases, decreased microvessel density and levels of tumor-associated macrophages, and increased natural killer cells in mice. Depletion of RNF2 or BMI1 also suppressed the formation of tumor spheres in vitro.
Lastly, the researchers reported that GW-516 inhibited the outgrowth of bone, brain, and liver metastases in mice. When combined with double-checkpoint immunotherapy, metastases in mice were completely suppressed; levels of tumor-associated macrophages, regulatory T cells, and neoangiogenesis were decreased, with a concomitant increase in CD4-positive and CD8-positive T cells in mouse and in vitro models.
“We envision that targeting PRC1 may sensitize [metastatic castration-resistant prostate cancer] and other immunologically ‘cold’ cancer types to immunotherapy,” the authors concluded.
Disclosure: The study authors’ disclosure information can be found at cell.com.