PT  - JOURNAL ARTICLE
AU  - Srinivas Animireddy
AU  - Padmavathi Kavadipula
AU  - Viswakalyan Kotapalli
AU  - Swarnalata Gowrishankar
AU  - Satish Rao
AU  - Murali Dharan Bashyam
TI  - Cytoplasm localized ARID1B promotes oncogenesis in pancreatic cancer by activating RAF-ERK signaling
AID  - 10.1101/830075
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 830075
4099  - http://biorxiv.org/content/early/2019/11/07/830075.short
4100  - http://biorxiv.org/content/early/2019/11/07/830075.full
AB  - The ARID1B/BAF250b subunit of the human SWI/SNF chromatin remodeling complex is a canonical nuclear tumor suppressor. Immunohistochemistry on a pancreatic cancer tissue microarray revealed significant ARID1B cytoplasmic localization that correlated with advanced tumor stage and lymph node positivity. Identification of the nuclear localization signal (NLS) using in silico prediction and subcellular localization studies facilitated evaluation of a possible cytoplasmic function for ARID1B. A cytoplasm-restricted ARID1B-NLS mutant was significantly compromised to regulate transcription activation and tumor suppression functions, as expected. Surprisingly however, cytoplasm-localized ARID1B could bind c-RAF and PPP1CA causing stimulation of RAS-RAF-ERK signaling and β-catenin transcription activity in pancreatic cancer cells. More importantly, cytoplasmic ARID1B resulted in an induction of cell growth and migration in pancreatic cancer cell lines that was dependent on ERK signaling and caused increased tumorigenesis in nude mice. NLS peptides representing mutations identified from pancreatic cancer samples exhibiting ARID1B cytoplasmic localization or curated from cancer somatic mutation database were significantly compromised to effect nuclear localization of a reporter protein. ARID1B cytoplasmic localization correlated significantly with active forms of ERK and β-catenin in primary pancreatic tumor samples. ARID1B may therefore promote oncogenesis through non-canonical cytoplasm-based gain of function mechanisms in addition to dysregulation in the nucleus.