Histone acetyltransferase 1 promotes gemcitabine resistance by regulating the PVT1/EZH2 complex in pancreatic cancer

The poor prognosis of pancreatic cancer is primarily due to the development of resistance to therapies, including gemcitabine. The long noncoding RNA PVT1 (lncRNA PVT1) has been shown to interact with enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2), promoting gemcitabine resistance in pancreatic cancer. In this study, we found histone acetyltransferase 1 (HAT1) enhanced the tolerance of pancreatic cancer cells to gemcitabine and HAT1-mediated resistance mechanisms were regulated by PVT1 and EZH2. Our results showed that the aberrant HAT1 expression promoted gemcitabine resistance, while silencing HAT1 restored gemcitabine sensitivity. Moreover, HAT1 depletion caused a notable increase of gemcitabine sensitivity in gemcitabine-resistant pancreatic cancer cell lines. Further research found that HAT1 increased PVT1 expression to induce gemcitabine resistance, which enhanced the binding of bromodomain containing 4 (BRD4) to the PVT1 promoter, thereby promoting PVT1 transcription. Besides, HAT1 prevented EZH2 degradation by interfering with ubiquitin protein ligase E3 component n-recognin 4 (UBR4) binding to the N-terminal domain of EZH2, thus maintaining EZH2 protein stability to elevate the level of EZH2 protein, which also promoted HAT1-mediated gemcitabine resistance. These results suggested that HAT1 induced gemcitabine resistance of pancreatic cancer cells through regulating PVT1/EZH2 complex. Given this, Chitosan (CS)-tripolyphosphate (TPP)-siHAT1 nanoparticles were developed to block HAT1 expression and improve the antitumor effect of gemcitabine. The results showed that CS-TPP-siHAT1 nanoparticles augmented the antitumor effects of gemcitabine in vitro and in vivo. In conclusion, HAT1-targeted therapy can improve observably gemcitabine sensitivity of pancreatic cancer cells. HAT1 is a promising therapeutic target for pancreatic cancer.

Automated summary

The poor prognosis of pancreatic cancer is mainly due to resistance to therapies, including gemcitabine. Long noncoding RNA PVT1 (lncRNA PVT1) interacts with enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2), promoting gemcitabine resistance. Histone acetyltransferase 1 (HAT1) enhances pancreatic cancer cells' tolerance to gemcitabine, with mechanisms regulated by PVT1 and EZH2.