Loss of histone macroH2A1 in hepatocellular carcinoma cells promotes paracrine-mediated chemoresistance and CD4⁺CD25⁺FoxP3⁺ regulatory T cells activation

Abstract

Rationale: Loss of histone macroH2A1 induces appearance of cancer stem cells (CSCs)-like cells in hepatocellular carcinoma (HCC). How CSCs interact with the tumor microenvironment and the adaptive immune system is unclear.Methods: We screened aggressive human HCC for macroH2A1 and CD44 CSC marker expression. We also knocked down (KD) macroH2A1 in HCC cells, and performed integrated transcriptomic and secretomic analyses.Results: Human HCC showed low macroH2A1 and high CD44 expression compared to control tissues. MacroH2A1 KD CSC-like cells transferred paracrinally their chemoresistant properties to parental HCC cells. MacroH2A1 KD conditioned media transcriptionally reprogrammed parental HCC cells activated regulatory CD4+/CD25+/FoxP3+ T cells (Tregs).Conclusions: Loss of macroH2A1 in HCC cells drives cancer stem-cell propagation and evasion from immune surveillance.

Circulating histone signature of human lean metabolic-associated fatty liver disease (MAFLD)

“…Given the lack of diagnostic value of circulating nucleosomes for non-obese MAFLD, we sought to determine if, conversely, the diversity of circulating single histones (H2A, H2B, H3, H4, macroH2A1.1 and macroH2A1.2), and histone complexes [23][24][25][26][27][28][29][30][31] may be used as new biomarkers for lean MAFLD. ELISA assays can detect nucleosome or individual histones (one by one) in serum; however, a real-time high throughput assaying of multiple histones remains unexplored.…”

“…The members of the macroH2A group of H2A histone variants (macroH2A1 and macroH2A2) are the largest in nature [25]. Others and we have recently demonstrated that macroH2A1 isoforms play fundamental roles in modulating stem cell differentiation, MAFLD and HCC progression [26][27][28][29][30][31]. It is unknown whether individual diverse circulating histone complexes may be used as biomarkers for lean MAFLD.…”

A Lipidomic Signature Complements Stemness Features Acquisition in Liver Cancer Cells

“…Accordingly, it appears that CSCs are extremely reliant on the activity of the enzymes involved in these processes, such as stearoyl-CoA desaturase 1 (SCD1) and 3-hydroxy-3-methylglutharyl-coenzyme A reductase (HMG-CoAR) [ 15 ]. In addition, increase in extracellular lipid uptake contributes to lipid droplets (LDs) accumulation and tumor initiation capacity in CSCs [ 16 ], a phenomenon that we have recently described for the first time in liver CSCs [ 17 , 18 , 19 ]. Whereas therapeutic strategies to eradicate nonhepatic CSCs based on their aberrant lipid metabolism have been envisaged [ 20 ], a lipid marker signature of liver CSCs obtained through high-throughput mass spectrometry (MS)-based lipidomics remains elusive, and it could guide novel therapeutic approaches.…”

“…Whereas therapeutic strategies to eradicate nonhepatic CSCs based on their aberrant lipid metabolism have been envisaged [ 20 ], a lipid marker signature of liver CSCs obtained through high-throughput mass spectrometry (MS)-based lipidomics remains elusive, and it could guide novel therapeutic approaches. In the present study, we characterize the levels of the members of the six major classes of sphingolipids and phospholipids [Cer, PC, lysophosphatidylcholine (LPC), PE, lysophosphatidylethanolamine (LPE), SM] in two HCC cell lines: HepG2 and Huh-7 were either silenced for the expression of histone variant macroH2A1, which contributes to transform them in liver CSC-like cells [ 17 , 18 , 19 ], or silenced for the expression of focal adhesion tyrosine kinase (FAK), which in turn is capable of inhibiting their aggressiveness and stemness [ 21 , 22 ].…”

The diagnostic and prognostic value of H2AFY in hepatocellular carcinoma

“…In recent years, more and more studies have shown that H2AFY is differentially expressed and plays corresponding biological functions in multiple tumour types, including HCC, lung cancer, prostate cancer, acute myeloid leukaemia (AML), melanoma, and colon cancer (15,(26)(27)(28)(29)(30). According to previously published studies, the role of H2AFY in tumours is very complex and it is very challenging to study H2AFY in tumours.…”