理解错义与无义:肿瘤细胞劫持突变诱导的抑癌因子错误定位

The SWI/SNF chromatin remodeler utilizes energy of ATP hydrolysis to slide or evict nucleosomes or histones, thus enabling nuclear processes by driving an ‘open' chromatin architecture. The mammalian SWI/SNF, also termed the BrG1/Brm associated factor (BAF) complex, is the major chromatin remodeler in ontogeny and adult life. Three biochemically distinct BAF complexes namely canonical (cBAF), polybromo (PBAF), and non-canonical (ncBAF) have been characterized. BAF components, classified as canonical nuclear tumor suppressors, exhibit frequent inactivating mutations in cancers. Though, several studies have evaluated the functioning of BAF subunits, very few have attempted to characterize the role of BAF component mutation identified across cancer types. In our previous studies, we identified early-onset rectal cancer specific truncation mutations in the gene encoding the PBAF component ‘A-T rich interaction domain containing 2' ( ARID2 ), precluding its nucleal localization signal (NLS). These truncations were also identified across cancer types based on analysis of cancer mutation databases. NLS-inactivated ARID2 exhibited cytoplasmic localization (cARID2) and promoted tumorigenesis in colorectal, breast and lung cancer cell lines. Here, we present detailed mechanistic characterization of ARID2 truncations, presumed to be inactivating in nature, but exhibiting a gain of oncogenic function. We show that the glutamine rich GLN domain (amino acids 793-1128) is essential for the oncogenic function of cARID2. Tandem affinity purification mass spectrometry identified PBAF components in the interactome of wild-type but not of cARID2, as expected. More importantly, a novel interaction between cARID2 (but not wild type ARID2) and AKAP8L, validated using biochemical approaches. cARID2 devoid of the GLN domain, did not interact with AKAP8L. AKAP8L belongs to the AKAP95 domain containing family of proteins that interact with and activate protein kinase A (PKA) leading to oncogenic activation of CREB signalling. Further, cARID2 effected an increase in the phosphorylated (active) form of CREB and in transcript levels of canonical CREB targets including ATF3, ATF4, and CREM, indicators of activation of the CREB signalling axis. AKAP8L itself was shown to activate oncogenesis in CRC cells. Analysis of RNA Sequencing is currently underway to confirm the activation of the PKA/CREB oncogenic signalling by cARID2. Nude mice xenograft assays are also underway to confirm the oncogenic potential of cARID2. Overall, the findings reveal a Yin-Yang tumor suppressor/oncogenic role for ARID2 in cancer, similar to our previous discovery for ARID1B, an ARID2 paralogue. More importantly, our study has revealed novel therapeutic options for tumors exhibiting cytoplasmic ARID2.