HDAC6 inhibitors sensitize non-mesenchymal triple-negative breast cancer cells to cysteine deprivation

Abstract

Triple-negative breast cancer (TNBC) is a highly malignant type of breast cancer and lacks effective therapy. Targeting cysteine-dependence is an emerging strategy to treat the mesenchymal TNBC. However, many TNBC cells are non-mesenchymal and unresponsive to cysteine deprivation. To overcome such resistance, three selective HDAC6 inhibitors (Tubacin, CAY10603, and Tubastatin A), identified by epigenetic compound library screening, can synergize with cysteine deprivation to induce cell death in the non-mesenchymal TNBC. Despite the efficacy of HDAC6 inhibitor, knockout of HDAC6 did not mimic the synthetic lethality induced by its inhibitors, indicating that HDAC6 is not the actual target of HDAC6 inhibitor in this context. Instead, transcriptomic profiling showed that tubacin triggers an extensive gene transcriptional program in combination with erastin, a cysteine transport blocker. Notably, the zinc-related gene response along with an increase of labile zinc was induced in cells by the combination treatment. The disturbance of zinc homeostasis was driven by PKCγ activation, which revealed that the PKCγ signaling pathway is required for HDAC6 inhibitor-mediated synthetic lethality. Overall, our study identifies a novel function of HDAC6 inhibitors that function as potent sensitizers of cysteine deprivation and are capable of abolishing cysteine-independence in non-mesenchymal TNBC.

Potential Role of APEX1 During Ferroptosis

“…Therefore, these transcription factors may be activated by APEX1, presumably through the same redox process. Besides, in order to further illustrate the potential molecular mechanism of APEX1 in ferroptosis, we analyzed transcriptome datasets downloaded from NCBI [GSE104462 ( 141 ) and GSE154425 ( 142 )]. It was found that under the action of special ferroptosis inducer erastin, the mRNA level of APEX1 was decreased compared to control group in HepG2 cells (GSE104462) ( Figure 4A ).…”

Two Sides of the Same Coin: Protein Kinase C γ in Cancer and Neurodegeneration

“…Typically, PKCγ is only expressed in neuronal cell types, particularly in the cerebral cortex, hippocampus, and cerebellum ( Saito et al, 1988 ; Saito and Shirai, 2002 ; Gomis-González et al, 2021 ). However, evidence for aberrant PKCγ expression has been established in certain cancer types, such as colon cancer and breast cancer ( Parsons and Adams, 2008 ; Garczarczyk et al, 2010 ; Dowling et al, 2017 ; Alothaim et al, 2021 ). Although the mechanism that triggers anomalous PKCγ expression in cancer remains unclear, several studies have addressed the role of PKCγ in these cell types.…”

“…Parsons and Adams elucidated a possible mechanism by which aberrantly expressed PKCγ may promote colon cancer cell migration, showing that PKCγ interacted with the tumor-promoting fascin ( Parsons and Adams, 2008 ). On the other hand, in the context of triple negative breast cancer (TNBC), PKCγ has been shown to promote HDAC6 inhibitor-mediated lethality of non-mesenchymal TNBC ( Alothaim et al, 2021 ). Thus, some studies have led to the conclusion that PKC promotes growth, but other factors, like mutations in PKCγ, have not been accounted for.…”

Recurrent triple-negative breast cancer from cysteine deprivation loses tumorigenicity via downregulation of the CST4 signaling

“…Breast cancer shows differentiated sensitivity to targeted cysteine therapy partially due to intertumoral heterogeneity. For example, the mesenchymal-type TNBC is highly sensitive to erastin, an inhibitor of xCT, while the epithelial-type TNBC is irresponsive [25,33]. Epigenetic sensitizers have been identified to overcome the erastin-resistance in the epithelial TNBC [33].…”

“…For example, the mesenchymal-type TNBC is highly sensitive to erastin, an inhibitor of xCT, while the epithelial-type TNBC is irresponsive [25,33]. Epigenetic sensitizers have been identified to overcome the erastin-resistance in the epithelial TNBC [33]. Other mechanisms contributing to the erastin-resistance have been suggested in some cancers, such as activation of NRF2/CBS in ovarian cancer [34], degradation of VDAC2/3 melanoma [35], hypoxia, and extracellular cysteinyl glycine in glioblastoma [36], and deregulated cellular signaling in breast cancer [37][38].…”