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 overco...

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Autores principales:	Tahiyat Alothaim, Morgan Charbonneau, Xiaohu Tang
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/0b8f1972d0a84bcd92e515fb61b1ef28
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spelling	oai:doaj.org-article:0b8f1972d0a84bcd92e515fb61b1ef282021-12-02T14:49:12ZHDAC6 inhibitors sensitize non-mesenchymal triple-negative breast cancer cells to cysteine deprivation10.1038/s41598-021-90527-62045-2322https://doaj.org/article/0b8f1972d0a84bcd92e515fb61b1ef282021-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-90527-6https://doaj.org/toc/2045-2322Abstract 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.Tahiyat AlothaimMorgan CharbonneauXiaohu TangNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-11 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Tahiyat Alothaim Morgan Charbonneau Xiaohu Tang HDAC6 inhibitors sensitize non-mesenchymal triple-negative breast cancer cells to cysteine deprivation
description	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.
format	article
author	Tahiyat Alothaim Morgan Charbonneau Xiaohu Tang
author_facet	Tahiyat Alothaim Morgan Charbonneau Xiaohu Tang
author_sort	Tahiyat Alothaim
title	HDAC6 inhibitors sensitize non-mesenchymal triple-negative breast cancer cells to cysteine deprivation
title_short	HDAC6 inhibitors sensitize non-mesenchymal triple-negative breast cancer cells to cysteine deprivation
title_full	HDAC6 inhibitors sensitize non-mesenchymal triple-negative breast cancer cells to cysteine deprivation
title_fullStr	HDAC6 inhibitors sensitize non-mesenchymal triple-negative breast cancer cells to cysteine deprivation
title_full_unstemmed	HDAC6 inhibitors sensitize non-mesenchymal triple-negative breast cancer cells to cysteine deprivation
title_sort	hdac6 inhibitors sensitize non-mesenchymal triple-negative breast cancer cells to cysteine deprivation
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/0b8f1972d0a84bcd92e515fb61b1ef28
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HDAC6 inhibitors sensitize non-mesenchymal triple-negative breast cancer cells to cysteine deprivation

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