The ARID1B/BAF250b subunit of the human SWI/SNF chromatin remodeling complex is a canonical nuclear tumor suppressor. We employed in silico prediction, intracellular fluorescence and cellular fractionation based subcellular localization analyses to identify the ARID1B nuclear localization signal. A cytoplasm-restricted ARID1B-NLS mutant was significantly compromised in its canonical transcription activation and tumor suppressive functions, as expected. Surprisingly however, cytoplasmic localization appeared to induce a gain of oncogenic function in ARID1B as evidenced from several cell line and mouse xenograft based assays. Mechanistically, cytoplasm-localized ARID1B could bind c-RAF and PPP1CA causing stimulation of RAF-ERK signaling and β-catenin transcription activity. ARID1B harboring NLS mutations derived from tumor samples also exhibited aberrant cytoplasmic localization and acquired a neo-morphic oncogenic function via activation of RAF-ERK signaling. Further, immunohistochemistry on a tissue microarray revealed significant correlation of ARID1B cytoplasmic localization with increased levels of active forms of ERK1/2 and β-catenin as well as with advanced tumor stage and lymph node positivity in human primary pancreatic tumor tissues. ARID1B therefore promotes oncogenesis through cytoplasm-based gain of function mechanisms in addition to dysregulation in the nucleus.
The mammalian SWI/SNF complex is an ATP-dependent chromatin remodeler and master regulator in development that when mutated is the cause for several human diseases including cancer. Although SWI/SNF is highly enriched at enhancers and its basic chromatin remodeling activities have been studied for over 30 years, there is little known about how it regulates enhancer activity or enhancer-promoter interactions. We find a putative RNA binding module located near the C-terminus of the catalytic subunit of SWI/SNF required for SWI/SNF recruitment to cell-type specific enhancers and super-enhancers in naive and cell lineage primed pluripotent cells. The AT-hook is required for acquisition of the active histone marks H3K27ac and H3K4me1 and recruitment of the MLL3/4 co-activator to these enhancers and super-enhancers. Consistent with changes in enhancer architecture, loss of the AT-hook interferes with activation of genes involved in cell lineage priming as well as genes normally activated in naive pluripotent cells.
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