MacroH2A1 downregulation enhances the stem-like properties of bladder cancer cells by transactivation of Lin28B

Abstract

The histone variant, macroH2A1, has an important role in embryonic stem cell differentiation and tumor progression in various types of tumors. However, the regulatory roles of macroH2A1 on bladder cancer progression have not been fully elucidated. Here, we show that macroH2A1 knockdown promotes stem-like properties of bladder cancer cells. The knockdown of macroH2A1 in bladder cancer cells increased tumorigenicity, radioresistance, degeneration of reactive oxygen species, increased sphere formation capability and an increase in the proportion of side populations. We found that macroH2A1 is required for the suppression of Lin28B identified as a novel downstream target of macroH2A1 in bladder cancer. Loss of macroH2A1 expression significantly correlated with the elevated levels of Lin28B expression and subsequently inhibited the mature let-7 microRNA expression. Furthermore, the stable overexpression of Lin28B enhances the several phenotypes, including tumorigenicity and sphere-forming ability, which are induced by macroH2A1 depletion. Importantly, Lin28B expression was regulated by macroH2A1-mediated reciprocal binding of p300 and EZH2/SUV39H1. Our results suggest that Lin28B/let-7 pathway is tightly regulated by macroH2A1 and its cofactors, and have a pivotal role in the bladder tumor progression and the regulation of stem-like characteristics of bladder cancer cells.

QKI5-mediated alternative splicing of the histone variant macroH2A1 regulates gastric carcinogenesis

“…Similar to most macrodomains, macroH2A1.1's macrodomain can interact with NAD + -derived ligands, such as PAR, whereas the macrodomain of macroH2A1.2 cannot. This distinction is functionally important in cancer, in which reduction in macroH2A1.1 occurs in several tumor types and the alteration in macroH2A1.1 expression has important effects on both the proliferation and metastatic potential of cancer cells [18, 28]. In the present study, we demonstrated that macroH2A1.1 inhibited GC cell proliferation, migration, and invasion by repressing CCNL1 expression.…”

“…In general, macroH2A1.1 is associated with repressive heterochromatin, in which it colocalizes with other heterochromatin markers, such as histone H3 lysine 27 trimethylation (H3K27me3) [27, 28]. To define macroH2A1.1-regulated genes in GC cells, we compared the existing macroH2A1 ChIP-seq [29, 30] and RNA-seq [31] database and performed qPCR to validate these candidates in HGC-27 cells (Figure 6A).…”

Dysregulation of miRNAs in bladder cancer: altered expression with aberrant biogenesis procedure

“…Park et al . discover that in bladder cancer cells, the loss of the histone variant, macroH2A1, can significantly suppress the expression of mature let-7 via the upregulation of Lin 28 [85]. This result reconfirms what Lin et al .…”

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

“…Histone variants can have genome‐wide effects on transcription; therefore, we conducted unbiased comparative analyses of RNA‐sequencing data generated from control and macroH2A1 KD HCC cells to identify differentially expressed genes. A recent report showing a role for macroH2A1 in stemness of bladder tumor cell lines screened a panel of known CSC‐associated genes and suggested that the observed CSC phenotype was driven by the RNA‐binding protein LIN28B; in this tumor type, mRNA alternative splicing leads to macroH2A1.1, but not macroH2A1.2, down‐regulation, whereas in HCC alternative splicing of macroH2A1 seems to be irrelevant, this study. Confining the genomic action of macroH2A1 to the promoter of one gene (i.e., LIN28B) could be a reductive approach because genome occupancy of macroH2A1 covers large genomic domains in HepG2 cells and is not restricted to promoters .…”