YEATS4 promotes the tumorigenesis of pancreatic cancer by activating beta-catenin/TCF signaling

Abstract

Beta-catenin/TCF signaling has been reported to promote the growth and metastasis of pancreatic cancer cells. However, the regulation for the beta-catenin/TCF transcriptional complex remains largely unknown. Here, we have found that YEATS4 is a positive regulator for Beta-catenin/TCF signaling. The expression of YEATS4 was elevated in clinical pancreatic cancer samples and pancreatic cancer mouse model. Up-regulation of YEATS4 promoted the growth, migration and invasion of pancreatic cancer cells, while knocking down the expression of YEATS4 inhibited the growth, migration, invasion and metastasis of pancreatic cancer cells. Moreover, the mechanism study revealed that YEATS4 interacted with beta-catenin and activated beta-catenin/TCF signaling. Furthermore, knocking down the expression of YEATS4 impaired the malignant transformation of normal pancreatic cells (HPDE6C7) by the oncogenic Ras. Taken together, our study demonstrated the oncogenic roles of YEATS4 in the progression of pancreatic cancer by activating beta-catenin/TCF signaling and suggested that YEATS4 might be a promising therapeutic target for pancreatic cancer.

YEATS4 (YEATS domain containing 4)

“…YEATS4 transcript overexpression was noted in 31 pancreatic cancer samples relative to adjacent noncancerous tissues (Jixiang et al, 2017). An expansion of this study to 93 pancreatic samples in the ONCOMINE database (Rhodes et al, 2004) further indicated clinical significance of YEATS4 expression in pancreatic cancer.…”

“…Further evidence for a function of YEATS4 in transcription has come from direct interactions with transcription factor TFAP2A (AP-2) (Ding et al, 2006), and the C-terminal region of the myc family members MYCN and MYC (Piccinni et al, 2011), identified by affinity capture techniques such as yeast two-hybrid analysis, GST-pull down and coimmunoprecipitation. The β-catenin gene (CTNNB1) is regulated by binding of YEATS4 to its promoter, either via these transcription factors, or in combination with the chromatin modeling complexes discussed above (Ji et al, 2017;Jixiang et al, 2017). Downstream targets of β-catenin such as CCND1 (Cyclin D1), CDK4, CDK6 and c-Myc, and the apoptotic proteins BCL2 and BAX also respond to overexpression and decreased expression of YEATS4 in gastric cancer and pancreatic cancer (Ji et al, 2017;Jixiang et al, 2017).…”

“…The β-catenin gene (CTNNB1) is regulated by binding of YEATS4 to its promoter, either via these transcription factors, or in combination with the chromatin modeling complexes discussed above (Ji et al, 2017;Jixiang et al, 2017). Downstream targets of β-catenin such as CCND1 (Cyclin D1), CDK4, CDK6 and c-Myc, and the apoptotic proteins BCL2 and BAX also respond to overexpression and decreased expression of YEATS4 in gastric cancer and pancreatic cancer (Ji et al, 2017;Jixiang et al, 2017). As noted above, the Tip60 and SCRAP complex play roles in double-stranded DNA repair.…”

“…Introduction of YEATS4 into a normal pancreatic epithelial cell lines promote growth invasion and motility. These effects were mediated, at least in part, by activation of the Wnt pathway and direct interaction with beta catenin (Jixiang et al, 2017).…”

miR‑493 inhibits proliferation and invasion in pancreatic cancer cells and inversely regulated hERG1 expression

“…Although surgery is the primary way of treatment, pharmacological treatments are also an important adjuvant to surgery. During the past decades, studies have tried to understand the undelying molecular and signaling mechanisms that regulate the development of PC so that better therapy strategies may be developed ( 4 – 6 ).…”