Regulation of Breast Cancer-Induced Osteoclastogenesis by MacroH2A1.2 Involving EZH2-Mediated H3K27me3

Abstract

SUMMARY Breast cancer cells relocate to bone and activate osteoclast-induced bone resorption. Soluble factors secreted by breast cancer cells trigger a cascade of events that stimulate osteoclast differentiation in the bone microenvironment. MacroH2A is a unique histone variant with a C-terminal non-histone domain and plays a crucial role in modulating chromatin organization and gene transcription. Here, we show that macroH2A1.2, one of the macroH2A isoforms, has an intrinsic ability to inhibit breast cancer- derived osteoclastogenesis. This repressive effect requires macroH2A1.2-dependent attenuation of expression and secretion of lysyl oxidase (LOX) in breast cancer cells. Furthermore, our mechanistic studies reveal that macroH2A1.2 physically and functionally interacts with the histone methyltrans- ferase EZH2 and elevates H3K27me3 levels to keep LOX gene in a repressed state. Collectively, this study unravels a role for macroH2A1.2 in regulating osteoclastogenic potential of breast cancer cells, suggesting possibilities for developing therapeutic tools to treat osteolytic bone destruction.

A three layered histone epigenetics in breast cancer metastasis

“…MacroH2A is another H2A variant that has been implicated in breast cancer metastasis [95]. It has two variants namely MacroH2A1 and MacroH2A2 encoded by H2AFY and H2AFY2 respectively [96]. Mac-roH2A1 has again two splice variants MacroH2A1.1 and MacroH2A1.2 [96,97].…”

“…It has two variants namely MacroH2A1 and MacroH2A2 encoded by H2AFY and H2AFY2 respectively [96]. Mac-roH2A1 has again two splice variants MacroH2A1.1 and MacroH2A1.2 [96,97]. The only difference between both of these splice variant is that MacroH2A1.2 lacks the Leucine zipper motif present in macroH2A1.1 [98].…”

“…Multiple studies have reported the tumour suppressor role of MacroH2A in breast can-cer [95]. MacroH2A1 expression is inversely related to aggressiveness of breast cancer cell lines [95,96]. Splice variant MacroH2A1.2 recruits EZH2 which trimethylates H3K27, leading to the formation of repressive chromatin mark around LOX (lysyl oxide) transcription start site [96].…”

“…MacroH2A1 expression is inversely related to aggressiveness of breast cancer cell lines [95,96]. Splice variant MacroH2A1.2 recruits EZH2 which trimethylates H3K27, leading to the formation of repressive chromatin mark around LOX (lysyl oxide) transcription start site [96]. LOX has been considered to be a major factor for breast cancer bone metastasis.…”

“…In cancer cells, depletion of MacroH2A1.2 leads to LOX upregulation that inhibit metastasis via c-Src signaling pathway ( Fig. 3bi) [96].…”