Histone 2A Family Member J Drives Mesenchymal Transition and Temozolomide Resistance in Glioblastoma Multiforme

Abstract

Glioblastoma multiforme (GBM) is the most aggressive brain tumor and has a poor prognosis and is poorly sensitive to radiotherapy or temozolomide (TMZ) chemotherapy. Therefore, identifying new biomarkers to predict therapeutic responses of GBM is urgently needed. By using The Cancer Genome Atlas (TCGA) database, we found that the upregulation of histone 2A family member J (H2AFJ), but not other H2AFs, is extensively detected in the therapeutic-insensitive mesenchymal, IDH wildtype, MGMT unmethylated, or non-G-CIMP GBM and is associated with poor TMZ responsiveness independent of radiation. Similar views were also found in GBM cell lines. Whereas H2AFJ knockdown diminished TMZ resistance, H2AFJ overexpression promoted TMZ resistance in a panel of GBM cell lines. Gene set enrichment analysis (GSEA) revealed that H2AFJ upregulation accompanied by the activation of TNF-α/NF-κB and IL-6/STAT3-related pathways is highly predicted. Luciferase-based promoter activity assay further validated that the activities of NF-κB and STAT3 are causally affected by H2AFJ expression in GBM cells. Moreover, we found that therapeutic targeting HADC3 by tacedinaline or NF-κB by ML029 is likely able to overcome the TMZ resistance in GBM cells with H2AFJ upregulation. Significantly, the GBM cohorts harboring a high-level H2AFJ transcript combined with high-level expression of TNF-α/NF-κB geneset, IL-6/STAT3 geneset or HADC3 were associated with a shorter time to tumor repopulation after initial treatment with TMZ. These findings not only provide H2AFJ as a biomarker to predict TMZ therapeutic effectiveness but also suggest a new strategy to combat TMZ-insensitive GBM by targeting the interaction network constructed by TNF-α/NF-κB, IL-6/STAT3, HDAC3, and H2AFJ.

Histone Variant H2A.J Is Enriched in Luminal Epithelial Gland Cells

“…H2AFJ was reported to be over-expressed in some cancers [7][8][9]11], and interrogation of the Cancer Genome Atlas (TCGA) database showed that prostate and breast cancer expressed high levels of H2AFJ mRNA (Figure 4, left panel). H2AFJ RNA was also highly expressed in many cancer cell lines derived from glandular tissues such as the breast, pancreas, lung, colorectum, thyroid, esophagus, stomach, and prostate according to the Broad Cancer Cell Line Encyclopedia (CCLE) (Figure 4, right panel).…”

“…H2A.J has been implicated in the expression of inflammatory genes in senescent fibroblasts [5,6]. H2A.J over-expression has also been implicated in luminal-B breast cancer tumorigenesis [7,8] and in the chemotherapeutic resistance of colorectal [9], hepatic [10], and glioblastoma cancers [11]. We performed a global survey of H2A.J expression in human and mouse tissues to obtain initial indications regarding potential tissue-specific functions.…”

Mesenchymal Transformation: The Rosetta Stone of Glioblastoma Pathogenesis and Therapy Resistance

“…[ 117 ] Other studies demonstrated that the histone 2A family member J (H2AFJ) is involved in TMZ resistance and MES transformation through NF‐ κ B and STAT3‐dependent signaling. [ 118,119 ] GSCs can induce an immunosuppressive nature in TAM through mTOR‐dependent regulation of STAT3 and NF‐ κ B activity. [ 120 ] Our group recently reported that GSCs with MES subtype can force PN cells to switch into a MES phenotype by means of extracellular vesicles (EVs), [ 121 ] a small vesicle released by practically every cell.…”

Mechanisms of temozolomide resistance in glioblastoma - a comprehensive review

“…Furthermore, they showed that inhibition of STAT3 increased TMZ-induced G 0 -G 1 arrest and decreased cyclin D1 expression compared to TMZ alone. A more recent study pointed to histone 2A family members (H2AFs) as components of nucleosomes crucial for gene regulation in the host [ 133 ] . This group found that H2AFJ, but not other H2AFs, is commonly found and upregulated in mesenchymal-type GBM tumors, compared to its expression in normal tissues derived from GBM patients [ 28 ] .…”