Induction of cancer cell stemness by depletion of macrohistone H2A1 in hepatocellular carcinoma

Re, Oriana Lo; Fusilli, Caterina; Rappa, Francesca; Haele, Matthias Van; Douet, Julien; Pindjáková, Jana; Rocha, Sura Wanessa Santos; Pata, Illar; Valčíková, Barbora; Uldrijan, Stjepan; Yeung, Raymond S.; Peixoto, Christina Alves; Roskams, Tania; Buschbeck, Marcus; Mazza, Tommaso; Vinciguerra, Manlio

doi:10.1002/hep.29519

Cited by 63 publications

(88 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Most research efforts have focused on DNA methylation and posttranslational modification of canonical histones H2A, H2B, H3, and H4. We recently investigated the loss of the histone variant macroH2A1a as a mechanism that increases CSClike properties of hepatic cancer cells [7]. MacroH2A1 is an histone variant of the H2A histone family that contains a histone-fold domain with 66% identity to replication-coupled histone H2A, and a C-terminal linker that connects the histone fold domain to a macro domain [8].…”

Section: Introductionmentioning

confidence: 99%

Histone variant macroH2A1 rewires carbohydrate and lipid metabolism of hepatocellular carcinoma cells towards cancer stem cells

Douet

Buschbeck

et al. 2018

Epigenetics

Self Cite

View full text Add to dashboard Cite

Hepatocellular carcinomas (HCCs) contain a sub-population of cancer stem cells (CSCs) that are responsible for tumor relapse, metastasis, and chemoresistance. We recently showed that loss of macroH2A1, a variant of the histone H2A and an epigenetic regulator of stem-cell function, in HCC leads to CSC-like features such as resistance to chemotherapeutic agents and growth of large and relatively undifferentiated tumors in xenograft models. These HCC cells silenced for macroH2A1 also exhibited stem-like metabolic changes consistent with enhanced glycolysis. However, there is no consensus as to the metabolic characteristics of CSCs that render them adaptable to microenvironmental changes by conveniently shifting energy production source or by acquiring intermediate metabolic phenotypes. Here, we assessed long-term proliferation, energy metabolism, and central carbon metabolism in human hepatoma HepG2 cells depleted in macroH2A1. MacroH2A1-depleted HepG2 cells were insensitive to serum exhaustion and showed two distinct, but interdependent changes in glucose and lipid metabolism in CSCs: (1) massive upregulation of acetyl-coA that is transformed into enhanced lipid content and (2) increased activation of the pentose phosphate pathway, diverting glycolytic intermediates to provide precursors for nucleotide synthesis. Integration of metabolomic analyses with RNA-Seq data revealed a critical role for the Liver X Receptor pathway, whose inhibition resulted in attenuated CSCs-like features. These findings shed light on the metabolic phenotype of epigenetically modified CSC-like hepatic cells, and highlight a potential approach for selective therapeutic targeting.

show abstract

Section: Introductionmentioning

confidence: 99%

Histone variant macroH2A1 rewires carbohydrate and lipid metabolism of hepatocellular carcinoma cells towards cancer stem cells

Douet

Buschbeck

et al. 2018

Epigenetics

Self Cite

View full text Add to dashboard Cite

show abstract

“…An increased number of senescent cells are associated not only to chemotherapeutic treatment but also to age‐related tissue degeneration towards HCC . In mice, impaired immune surveillance of senescent hepatocytes induces HCC, indicating that senescence surveillance is important for tumour suppression in the liver .…”

Section: Discussionmentioning

confidence: 99%

“…This concentration is only slightly cytotoxic to HCC cells, inducing senescence in ~40% of cells. 9,15,19 We then washed out the DXR and incubated the cells in normal medium for a further 5 days. Upon trypsin-mediated cell detachment,…”

Section: Iodixanol Density Gradient-based Centrifugation Separates mentioning

confidence: 99%

Isolation of senescent cells by iodixanol (OptiPrep) density gradient‐based separation

Kovacovicova

Vinciguerra

2019

Cell Proliferation

Self Cite

View full text Add to dashboard Cite

Objectives Chemotherapeutic drugs induce senescence in cancer cells but, unlike replicative senescence or oncogene‐induced senescence, do so rather inefficiently and depending on DNA damage. A thorough understanding of the biology of chemotherapy‐induced senescent cells requires their isolation from a mixed population of adjacent senescent and non‐senescent cancer cells. Materials and methods We have developed and optimized a rapid iodixanol (OptiPrep)‐based gradient centrifugation system to identify, isolate and characterize doxorubicin (DXR)‐induced senescent hepatocellular carcinoma (HCC) cells (HepG2 and Huh‐7) in vitro. Results After cellular exposure to DXR, we used iodixanol gradient‐based centrifugation to isolate and re‐plate cells on collagen‐coated flasks, despite their low or null proliferative capacity. The isolated cell populations were enriched for DXR‐induced senescent HCC cells, as confirmed by proliferation arrest assay, and β‐galactosidase and DNA damage‐dependent γH2A.X staining. Conclusions Analysing pure cultures of chemotherapy‐induced senescent versus non‐responsive cancer cells will increase our knowledge on chemotherapeutic mechanisms of action, and help refine current therapeutic strategies.

show abstract

“…Recent studies have reported the inactivation of somatic mutations in gene-encoding BRCA-1-associated protein 1 (BAP1) in about 84% of metastasizing UMs [14]: the high frequency of BAP1 mutations in metastatic UMs encouraged us to search for new therapeutic strategies with the target molecule BAP1, which have deubiquitinase activity on histone H2A [15,16]. In different tumors, including skin melanoma, mH2A and its variants, which are widely distributed along chromatin [17][18][19], have been regarded as a potential prognostic marker [20,21].…”

Section: Discussionmentioning

confidence: 99%

Immunoexpression of Macroh2a in Uveal Melanoma

et al. 2019

View full text Add to dashboard Cite

MacroH2A is a histone variant whose expression has been studied in several neoplasms, including cutaneous melanomas (CMs). In the literature, it has been demonstrated that macroH2A.1 levels gradually decrease during CM progression, and a high expression of macroH2A.1 in CM cells relates to a better prognosis. Although both uveal and cutaneous melanomas arise from melanocytes, uveal melanoma (UM) is biologically and genetically distinct from the more common cutaneous melanoma. Metastasis to the liver is a frequent occurrence in UM, and about 40%-50% of patients die of metastatic disease, even with early diagnosis, proper treatment, and close follow-up. We wanted to investigate macroH2A.1 immunohistochemical expression in UM. Our results demonstrated that mH2A.1 expression was higher in metastatic UM (21/23, 91.4%), while only 18/32 (56.3%). UMs without metastases showed mH2A.1 staining. These data could suggest a possible prognostic role for mH2A.1 and could form a basis for developing new pharmacological strategies for UM treatment.

show abstract

Induction of cancer cell stemness by depletion of macrohistone H2A1 in hepatocellular carcinoma

Abstract: The absence of histone variant macroH2A1 confers a CSC-like phenotype to HCC cells in vitro and in vivo that depends on Ser536 phosphorylation of nuclear factor kappa B p65; this pathway may hold valuable targets for the development of CSC-focused treatments for HCC. (Hepatology 2017).

Cited by 63 publications

References 39 publications

Histone variant macroH2A1 rewires carbohydrate and lipid metabolism of hepatocellular carcinoma cells towards cancer stem cells

Histone variant macroH2A1 rewires carbohydrate and lipid metabolism of hepatocellular carcinoma cells towards cancer stem cells

Isolation of senescent cells by iodixanol (OptiPrep) density gradient‐based separation

Immunoexpression of Macroh2a in Uveal Melanoma

Contact Info

Product

Resources

About