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

Abstract

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.

BIG Modulates Stem Cell Niche and Meristem Development via SCR/SHR Pathway in Arabidopsis Roots

“…To govern cell adhesion in human cells, pRB and UBR4 interact directly and co-localize in the nucleus [ 24 ]. UBR4 is a UBR box E3 ligase that uses the N-degron pathway to degrade proteins [ 24 , 25 , 26 , 27 ]. Sequence similarity analysis reveals that BIG has the conserved UBR box and E3 ligase domains ( Figure S2A ), pointing to a scenario that BIG might also regulate RBR levels through the N-degron pathway.…”

“…Ubiquitin protein ligase E3 component N-recognin 4 (UBR4) is a 600-kDa calmodulin-interacting protein involved in the N-end rule pathway [ 24 , 25 , 26 , 27 ]. BIG was originally identified in a mutational screen for resistance against N-1-naphthylphthalamic acid (NPA), a potent auxin transport inhibitor [ 28 ].…”

lncRNA PVT1: a novel oncogene in multiple cancers

“…Another study by Sun et al. [ 115 ] showed that HAT1 improves the resistance of PC to chemotherapy by promoting PVT1 expression and inhibiting EZH2 degradation. Moreover, You et al.…”

“…1C) [56]. Wan et al [42] demonstrated that PVT1 repressed the expression of LAST2 by recruiting EZH2 to the Pancreatic cancer Upregulation Oncogene Progression and glycolysis miR-519d-3p HIF-1A [111] Pancreatic cancer Upregulation Oncogene Autophagy miR-20a-5p ULK1 [113] Pancreatic cancer Upregulation Oncogene Chemoresistance / EZH2 [115] Pancreatic cancer Upregulation Oncogene Proliferation miR-1207 / [116] Pancreatic cancer Upregulation Oncogene Chemoresistance miR-409 SHH/GLI/MGMT [117] Pancreatic cancer Upregulation Oncogene Chemoresistance miR-619-5p Pygo2 [118] promoter region of LAST2. LAST2 is an upstream phosphokinase of the Hippo signaling pathway that can phosphorylate YAP1 to reduce its expression and activate the Hippo signaling pathway.…”

Long non-coding RNA PVT1: A promising chemotherapy and radiotherapy sensitizer

“…Simultaneously, HAT1 competitively binds to the N-terminus of EZH2 with the ubiquitin protein ligase E3 component n-recognin 4 (UBR4), preventing the ubiquitination of EZH2. Thus, HAT1 promotes gemcitabine resistance in pancreatic cancer cells (28). Based on this mechanism, tripolyphosphate (TPP)-siHAT1 nanoparticles have been developed to inhibit HAT1 expression and overcome gemcitabine resistance in pancreatic cancer cells.…”