Chromatin complexes subunit BAP18 promotes triple-negative breast cancer progression through transcriptional activation of oncogene S100A9

Abstract

Triple-negative breast cancer (TNBC) is a highly lethal disease due to aggressive clinical phenotype and the lack of validated therapeutic targets. Our recent quantitative proteomic analysis of 90 cases of TNBC tissues and 72 cases of matched adjacent normal tissues revealed that the expression levels of BPTF-associated protein of 18 KDa (BAP18), a component of the MLL1 and NURF chromatin complexes, were upregulated in TNBC tissues relative to normal tissues. However, the biological function and the underlying mechanism of BAP18 in TNBC progression remain unexplored. Here, we report that BAP18 promoted TNBC cell proliferation, migration, and invasion in vitro and xenograft tumor growth and lung colonization in vivo. Mechanistic investigations revealed that S100 calcium-binding protein A9 (S100A9), a member of the S100 protein family that is frequently upregulated in breast tumors and acts as an oncogenic driver in breast cancer progression, was a downstream target gene of BAP18. BAP18 was recruited to histone H3 trimethylation at lysine 4 (H3K4me3)-marked promoter of S100A9 and enhanced its promoter activities. Notably, knockdown of BAP18 by short hairpin RNA in TNBC cells suppressed xenograft tumor growth in mice, the noted effect was partially reverted by re-expression of S100A9 in BAP18-depleted cells. Taken together, these results suggest that BAP18 promotes TNBC progression through, at least in part, transcriptional activation of oncogene S100A9, and represents a potential therapeutic target for TNBC.

TRIB3 Modulates PPARγ-Mediated Growth Inhibition by Interfering with the MLL Complex in Breast Cancer Cells

“…BAP18 is a member of the MLL-WRAD complex, but also of the NURF complex [57], adding to the possibility that TRIB3 influences other major transcriptional regulatory complexes. In addition, BAP18 has been also implicated in triple-negative breast cancer development through the activation of the oncogene S100A9 [58]. All in all, this only strengthens our conclusion, as it shows TRIB3 as part of the interactome of MLL-WRAD proteins.…”

SF3A2 promotes progression and cisplatin resistance in triple-negative breast cancer via alternative splicing of MKRN1

“…Authentication and mycoplasma detection of the cell lines were performed before use. All cell lines were cultured as described previously ( 55 ) and used for less than 6 months within 15 to 20 passages. Detailed information regarding the chemical reagents and antibodies used in this study is provided in tables S1 and S2, respectively.…”

“…Immunoblotting assays were carried out as described in our previous study ( 55 ). For the IP assays, NP-40 buffer was used to lyse the cultured cells.…”

“…RNA-seq was performed as described previously ( 55 ). For AS analyses, differentially spliced exons and introns were identified using rMATS ( 58 ).…”

Hypoxia: syndicating triple negative breast cancer against various therapeutic regimens

“…These properties play a crucial role in tumor growth, immune evasion, metabolic reprogramming, drug resistance, and constraining clinical outcomes by modulating the transcription of several target genes (71). Hypoxia-activated pathways in the tumor microenvironment, such as HIF, CD133, CD24, CD47, DLK1, and mixed lineage leukemia 1 (MLL1), are the most essential contributing vital factors to CSC generation and maintenance (72)(73)(74). Increasing published evidences has supported and proved that HIF-1a is the central regulator of induction and maintenance of self-renewal and anti-apoptotic phenotypic properties of various CSCs such as octamer-binding transcription factor 4 (OCT4), SRY (sex determining region Y)-box 2 (SOX2), NANOG (encodes an NK2family homebox transcripton factor), and Krüppel-like factor 4 (KLF4) (35,75,76).…”