fdps Dysregulation or mutations of catenin are widespread in

Dysregulation or mutations of β-catenin are widespread in GIC, and altered β-catenin plays fundamental roles in GIC initiation and progression (Basu et al., 2016; Oguma et al., 2008; Vogelstein et al., 2013). By interacting with β-catenin, ASF1A thus exhibits multiple oncogenic activities, as documented in the present study. It promoted proliferation of CRC fdps by stimulating c-MYC and cyclin D1 expression, while inhibiting E-Cadherin expression via up-regulation of ZEB1, thereby augmenting cellular migration or invasion. Moreover, the CRC stem cell marker LGR5 increased coupled with the enhanced self-renewal potential in ASF1A-over-expressed CRC cells, suggesting its requirement for maintaining CRC stem cell phenotype. Thus, the ASF1A-β-catenin axis is functionally essential to GIC tumors and disruption of their interaction may have therapeutic implications. In addition to OCT4 and β-catenin, ASF1A has been shown to interact with other transcriptional regulators such as the histone acetyltransferase Creb-binding protein (CBP)/P300 and the transcription factor Mef2 (Das et al., 2009; Das et al., 2014). Furthermore, ASF1A is required for histone H3-K56 acetylation, while the H3-K56 acetylation state plays a key role in enabling rapid transcriptional changes (Das et al., 2009; Das et al., 2014). These data collectively indicate that ASF1A may be an important co-factor participating in transcriptional regulation by interacting and cooperating with transcription factors or their co-factors, and via modification of H3-K56. Likely, many more genes are transcriptionally controlled by ASF1A, and the elucidation of ASF1A target genes will gain profound insights into biological and oncogenic activities of ASF1A. Corpet et al. previously reported that ASF1B was required for proliferation of breast cancer cells, and higher ASF1B expression predicted poor patient outcomes, whereas ASF1A expression did not increase and contributed no prognostic information to breast cancer (Corpet et al., 2011). This observation is in contrast to what we found in GIC tumors. Thus it is likely that tumors derived from different tissues/organs utilize different isoforms of ASF1 for their malignant phenotype maintenance. The bromodomain and extra terminal domain (BET) family proteins including BRD3 and BRD4. They are another type of epigenetic modulators that read acetylated lysine residues and transfer cellular signals through which the transcription of oncogenes is augmented (Zuber et al., 2011). Small-molecule BET bromodomain inhibitors, for instance JQ1, have been developed to competitively bind to acetyl–lysine recognition pockets, and disrupt BET bromodomain protein interaction with chromatin, and subsequently reduce the expression of oncogenes, thereby leading to cancer cell growth inhibition and/or apoptosis (Zuber et al., 2011). Intriguingly, JQ1 was recently shown to inhibit H3-K56 acetylation (Das et al., 2014). H3-K56 acetylation is known to drive chromatin toward the disassembled state during transcriptional activation whereas loss of histone H3-K56 acetylation drives the chromatin toward the assembled state. It is thus necessary to elucidate whether JQ1-mediated blockade of H3-K56 acetylation is associated with its anti-cancer activity and whether there exists a cross-talk between BRDs and ASF1A.
Grant Support This work was supported by grants from The National Basic Research Program of China (grant no. 2012CB911202), Swedish Cancer Society (CAN 2016/427), the Swedish Research Council (#K2013-67X-14201-12-4), Cancer Society in Stockholm (141373), the National Natural Science Foundation of China (81070224, 81071721, 81000868 and 81171536), and Shandong Provincial Natural Science Foundation (2016ZDJS07A09). The funding sources have no roles in the writing of the manuscript or the decision to submit it for publication, data collection, analysis, or interpretation or patient recruitment. None of the authors have been paid to write this article by a pharmaceutical company or other agency.