BPTF inhibits NK cell activity and the abundance of natural cytotoxicity receptor co-ligands

Abstract

Using syngeneic BALB/c mouse breast cancer models, we show that the chromatin remodeling subunit bromodomain PHD finger transcription factor (BPTF) suppresses natural killer (NK) cell antitumor activity in the tumor microenvironment (TME). In culture, BPTF suppresses direct natural cytotoxicity receptor (NCR) mediated NK cell cytolytic activity to mouse and human cancer cell lines, demonstrating conserved functions. Blocking mouse NCR1 in vivo rescues BPTF KD tumor weights, demonstrating its importance for the control of tumor growth. We discovered that BPTF occupies heparanase (Hpse) regulatory elements, activating its expression. Increased heparanase activity results in reduced cell surface abundance of the NCR co-ligands: heparan sulfate proteoglycans (HSPGs). Using gain and loss of function approaches we show that elevated heparanase levels suppress NK cell cytolytic activity to tumor cells in culture. These results suggest that BPTF activates heparanase expression, which in turn reduces cell surface HSPGs and NCR co-ligands, inhibiting NK cell activity. Furthermore, gene expression data from human breast cancer tumors shows that elevated BPTF expression correlates with reduced antitumor immune cell signatures, supporting conserved roles for BPTF in suppressing antitumor immunity. Conditional BPTF depletion in established mouse breast tumors enhances antitumor immunity, suggesting that inhibiting BPTF could provide a novel immunotherapy.

WITHDRAWN: The chromatin remodeling complex NURF localizes to gene bodies and is required for mRNA processing.

“…Building on these discoveries, data we present suggest that NURF, as measured by localization of BPTF, is broadly localized to coding sequences in the genome and within the gene bodies. These results agree with previously reported localization of BPTF to gene bodies in human breast cancer cells (34), and from our own studies of BPTF as a regulator of tumor cell immunogenicity (50,51). Broad NURF localization is consistent with the proposed model of ISWI-containing remodeling complexes continuously sampling chromatin (52).…”

Bromodomain PHD‑finger transcription factor promotes glioma progression and indicates poor prognosis

“…Total proteins of fresh-frozen glioma and normal brain tissues were extracted using RIPA lysis buffer (Thermo Fisher Scientific, Inc.) and separated by 10% sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) then transferred onto polyvinylidene fluoride (PVDF) membranes (EMD Millipore, Billerica, MA, USA) as previously described ( 15 ). The protein concentration was detected by bicinchoninic acid (BCA) protein assay (Pierce Chemical, Rockford, IL, USA) according to the manufacturer's instructions.…”

Recent advances in searching c-Myc transcriptional cofactors during tumorigenesis

“…Investigation on its role in cancer showed that BTPF is overexpressed in lung cancer, where it plays an essential role in cell growth and survival by targeting many signaling pathways [ 43 ]. In addition, it has been demonstrated that NURF suppresses tumor antigenicity and that its depletion improves antigen processing enhancing T-cell-mediated antitumor immunity [ 44 , 45 ]. BPTF is mutated in bladder tumors and its knockdown in cultured bladder-cancer cells results in reduced proliferation and it is hypothesized that this effect is mediated in part by c-Myc [ 46 ].…”