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.
Highlights
Triple-negative breast cancer (TNBC) is a highly malignant type of breast cancer and lacks effective therapy
We found that ~ 50% of TNBCs are nonmesenchymal, and enriched expression of epithelial genes (Fig. S1A–C). These non-mesenchymal TNBC cells, such as HCC70 and HCC38, were cysteine-independent and resistant to erastin, a blocker of cysteine transport (Fig. S1D), distinct from mesenchymal HBL100 and MDA-MB-231 cells. To overcome such resistances in non-mesenchymal tumor cells and identify potential sensitizers, three inhibitors of the histone deacetylase 6 (HDAC6)—Tubacin, CAY10603, and Tubastatin A were identified by the epigenetic compound library screening, which dramatically induce synthetic-lethal death under the cysteine-depleted condition (Fig. 1A,B)
We found that Gö 6983, a protein kinase C (PKC) inhibitor with a broad inhibitory s pectrum[47], rescued cells from cell death induced by erastin and tubacin, while Gö 6976, a selective inhibitor of PKC α/β, had no protective role (Fig. 6A and Fig. S5A)
Summary
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. One classical example is that tumor cells acquire glycolysis (the Warburg effect) even under sufficient supply of oxygen. These tumors become addicted to glucose and are sensitive to inhibition of glycolysis by glucose analogues[19,20]. Cysteine deprivation or inhibition of cystine/glutamate antiporter (the system xC-) by erastin or sulfasalazine can limit the GSH synthesis, subsequently accumulate lipid peroxidative stress in cells and induce ferroptosis in cysteine-dependent tumor c ells[23]. Targeting cysteine-dependence could be an effective targeted cancer therapy, especially because limiting a single amino acid is a relatively feasible method for in vivo a pplication[30,31]. Little is known about the mechanisms that dictate the demand of cysteine in TNBC
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