Deacetylation of YAP1 Promotes the Resistance to Chemo- and Targeted Therapy in FLT3-ITD+ AML Cells

Abstract

The FLT3-ITD mutation occurs in about 30% of acute myeloid leukemia (AML) and is associated with poor prognosis. However, FLT3 inhibitors are only partially effective and prone to acquired resistance. Here, we identified Yes-associated protein 1 (YAP1) as a tumor suppressor in FLT3-ITD+ AML. YAP1 inactivation conferred FLT3-ITD+ AML cell resistance to chemo- and targeted therapy. Mass spectrometric assay revealed that DNA damage repair gene poly (ADP-ribose) polymerase 1 (PARP1) might be the downstream of YAP1, and the pro-proliferative effect by YAP1 knockdown was partly reversed via PARP1 inhibitor. Importantly, histone deacetylase 10 (HDAC10) contributed to decreased YAP1 acetylation levels through histone H3 lysine 27 (H3K27) acetylation, leading to the reduced nuclear accumulation of YAP1. Selective HDAC10 inhibitor chidamide or HDAC10 knockdown activated YAP1, enhanced DNA damage, and significantly attenuated FLT3-ITD+ AML cell resistance. In addition, combination chidamide with FLT3 inhibitors or chemotherapy agents synergistically inhibited growth and increased apoptosis of FLT3-ITD+ AML cell lines and acquired resistant cells from the relapse FLT3-ITD+ AML patients. These findings demonstrate that the HDAC10-YAP1-PARP1 axis maintains FLT3-ITD+ AML cells and targeting this axis might improve clinical outcomes in FLT3-ITD+ AML patients.

Extracellular Vesicles Derived circSH3PXD2A Inhibits Chemoresistance of Small Cell Lung Cancer by miR-375-3p/YAP1

“… 41–43 Downregulated expression of YAP1 accelerates resistance to chemotherapy and targeted drugs in FLT3-ITD + AML cells and docetaxel resistance in prostate cancer. 44 , 45 In our study, we confirmed that miR-375-3p targets YAP1. Our further research showed that circSH3PXD2A promotes YAP1 expression by sponging miR-375-3p and suppresses the chemoresistance of SCLC in vitro and in vivo.…”

DNA methylation landscape reveals GNAS as a decitabine-responsive marker in patients with acute myeloid leukemia

“…YAP plays a critical role in the pathogenesis of malignancies and it was recently shown to mediate resistance to chemotherapy in AML cells [ 18 , 19 ]. YAP is associated with cell growth and adhesion, lipogenesis, and numerous G-protein–coupled receptor ligands [19] .…”

HDAC10 inhibition represses melanoma cell growth and BRAF inhibitor resistance via upregulating SPARC expression

“…While these recent results clearly demonstrate that recombinant HDAC10 has negligible or low lysine deacetylase activity in vitro , some reports support earlier findings that HDAC10 catalyzes protein deacetylations. For instance, HDAC10 catalyzes the deacetylation of non-histone proteins including Hsc70/Hsp70 ( 98 ), EWSR1 ( 99 ), YAP1 ( 100 ), MSH2 ( 94 ) and hSSB1 ( 101 ). Conceivably, HDAC10 may associate with other HDACs to indirectly deacetylate proteins in living cells.…”