Functional cooperativity of p97 and histone deacetylase 6 in mediating DNA repair in mantle cell lymphoma cells

Abstract

p97 is an ATPase that works in concert with histone deacetylase 6 (HDAC6), to facilitate the degradation of misfolded proteins by autophagosomes. p97 has also been implicated in DNA repair and maintaining genomic stability. In this study we determined the effect of combined inhibition of p97 and HDAC6 activities in mantle cell lymphoma (MCL) cells. We report that treatment with p97 inhibitors induces dose-dependent apoptosis in MCL cells. The p97 inhibitor CB-5083 induces ER stress markers GRP78 and CHOP and results in the accumulation of polyubiquitylated proteins. Co-treatment with CB-5083 and the HDAC6 inhibitor ACY-1215 result in marked downregulation of CDK4, Cyclin D1 and BRCA1 levels without inhibiting autophagic flux. Consequently, treatment with CB-5083 accentuates DNA damage in response to treatment with ACY-1215 resulting in enhanced accumulation of H2AX-γ and synergistic apoptosis. Furthermore, ATM loss severely impairs phosphorylation of 53BP1 following co-treatment with CB-5083 and ACY-1215 in response to gamma irradiation. Finally, co-treatment CB-5083 and ACY-1215 results in reduced tumor volumes and improves survival in Z138C and Jeko-1 xenografts in NSG mice. These observations suggest that combined inhibition of p97 and HDAC6 abrogates resolution of proteotoxic stress and impairs DNA repair mechanisms in MCL cells.

<p>Delicaflavone Reverses Cisplatin Resistance via Endoplasmic Reticulum Stress Signaling Pathway in Non-Small Cell Lung Cancer Cells</p>

“…The resistance of lung cancer cells to DDP is a complex process, involving multiple factors and genes, including the mechanisms of the accumulation and deactivation of intracellular drugs, DNA damage repair, autophagy, and apoptosis. [14][15][16][17] Recently more and more research has focused on the mechanism of Delicaflavone in tumors. It exerts antitumor activity by inducing apoptosis and autophagy and Figure 2 Delicaflavone united with DDP regulated lung cancer DDP resistant cells invasion, migration.…”

“…5×10 3 /well A549, A549/DDP, PC9, and PC9/DDP cells were inoculated into 96 well plates for 12 h, then, the different concentrations of delicaflavone (5,10,20,40 and 80 µM) or DDP (2,4,8,16 and 32 µM) were added. In the meantime, A549/DDP cells were cultured with delicaflavone (20 µM) or DDP (16 µM) or delicaflavone (20 µM)+DDP (16 µM).…”

Actin-granule formation is an additional step in cardiac myofibroblast differentiation

“…In Staphylococcus aureus infection, GEF-H1 activity was blocked by HDAC6 down-regulation, and HDAC6 knockout and inhibition diminished ROCK-induced vascular leakage and inflammation (39). As a selective inhibitor of HDAC6, Ricolinostat has been proven to be of value attenuating oxidative stress to diminish inflammation and inducing apoptosis to inhibit tumor growth through various signaling pathways (40)(41)(42)(43). However, in this study Ricolinostat failed to prevent Ang II induced myofibroblast differentiation (a process accompanied by fibroblasts proliferation) and was discovered to promote GEF-H1 phosphorylation on Ser886 with enhanced activity of RhoA.…”

Histone Deacetylase 6 as a Therapeutic Target in B cell-associated Hematological Malignancies

“…The current clinical treatment of MCL is prone to drug resistance. It has recently been shown that combined treatment with ricolinostat and the P97 inhibitor CB-5083 leads to accumulation of ubiquitinated protein aggregates, ER stress ( Figure 1C), and increases DNA damage, ultimately resulting in apoptosis (Vekaria et al, 2019). In addition, the interaction between MCL or other NHL cells and their microenvironment confers tumor cell drug resistance and clonogenicity.…”

“…MCL originates from naive B cells ( Figure 1A ) and is characterized by dysregulation of cyclin D1 and DNA damage response pathways ( Nogai et al., 2011 ). p53 and cyclin D1 mutations and activation of the PI3K or NF-κB pathway lead to recurrence ( Vekaria et al., 2019 ). The current clinical treatment of MCL is prone to drug resistance.…”