Characterization of tumor suppressive function of P300/CBP-associated factor at frequently deleted region 3p24 in esophageal squamous cell carcinoma

Abstract

Deletion of 3p is one of the most frequent genetic alterations in many tumors, including esophageal squamous cell carcinoma (ESCC). In our recent study, deletion of 3p24 was frequently detected in ESCC and one candidate tumor suppressor gene (TSG), p300/CBP-associated factor (PCAF), was identified within the region. In this study, downregulation of PCAF was detected in 23/40 (57.5%) of primary ESCCs and 4/9 (44.4%) of the ESCC cell lines. A further study found that downregulation of PCAF was also associated with hypermethylation of the promoter region of PCAF gene. Methylation-specific PCR found that promoter methylation was detected in 28/40 (70%) of primary ESCCs and 5/9 (55.6%) of ESCC cell lines. In addition, the expression of PCAF could be reactivated in ESCC cell line KYSE510 after demethylation treatment with 5-azadC. Functional studies showed that PCAF was able to suppress tumorigenicity of ESCC cells both in vitro and in vivo, including foci formation, colony formation in soft agar and tumor formation in nude mice. Molecular study found that the tumor suppressive mechanism of PCAF was associated with its role in cell cycle arrest at the G1/S checkpoint by the downregulation of CDK2 and upregulation of p21 waf1/Cip1 , Smad4, Rb and p27 Kip1 . In conclusion, PCAF might be the target TSG responsible for the 3p24 deletion event, which has an important role in the development and progression of ESCC.

The histone acetyltransferase PCAF regulates p21 transcription through stress-induced acetylation of histone H3

“…Despite the normal development of PCAF-null mice, 55 likely due to compensation by GCN5, PCAF is downregulated through methylation or allelic loss in a variety of cancers. 56,57 Notably, PCAF induces G 1 arrest and inhibits soft agar growth and tumorigenesis upon its reintroduction into cell lines established from these tumors. While the levels of several key cell cycle regulators, including p21, were evaluated in these studies, the mechanistic role of PCAF in this activity was not explored further.…”

The p300/CBP - associated factor is frequently down-regulated in intestinal-type gastric carcinoma and constitutes a biomarker for clinical outcome

“…21 These observations further demonstrated PCAF may function as a tumor suppressor gene and a possible connection between PCAF and p53-p21 Waf1/Cip1 pathway.…”

A functional genomics screen identifies PCAF and ADA3 as regulators of human granzyme B-mediated apoptosis and Bid cleavage

“…We recently showed that overexpression of Bcl-2 and like inhibitors in tumor cells can potentially be overcome by combining hGrzB and a BH3-mimetic agent such as ABT-737 and that the hGrzB death signal is remarkably long lived. 39 The well-described capacity of various human cancers to downregulate PCAF or ADA3 levels [40][41][42][43] would be expected to blunt combination therapies such as this, by repressing the latent pro-apoptotic signal provided by tBid.…”

“…53 Finally, downregulation of PCAF has been observed in esophageal squamous cell carcinoma, ovarian and colorectal cancer. [40][41][42] Exactly how reduced expression and/or function of PCAF and ADA3 might lead to human diseases including cancer remains unclear. Small molecule inhibitors of PCAF have been reported; however, further studies on their specificity and role in disease are warranted 52,54 as is a further exploration of the potential impact of PCAF/ADA3 on immune-based cancer therapies.…”