Reprogrammed transsulfuration promotes basal-like breast tumor progression via realigning cellular cysteine persulfidation

Katalin Erdelyi, Tamas Ditroi, Henrik J. Johansson, Agnes Czikora, Noemi Balog, Laxmi Silwal-Pandit, Tomoaki Ida, Judit Olasz, Dorottya Hajdu, Zoltan Matrai, Orsolya Csuka, Koji Uchida, Jozsef Tovari, Olav Engebraten, Takaaki Akaike, Anne Lise Børresen Dale, Miklos Kasler, Janne Lehtio, Peter Nagy

Research output: Contribution to journalArticlepeer-review

Abstract

Basal-like breast cancer (BLBC) is the most aggressive subtype of breast tumors with poor prognosis and limited molecular-targeted therapy options.We show that BLBC cells have a high Cys demand and reprogrammed Cys metabolism. Patient-derived BLBC tumors from four different cohorts exhibited elevated expression of the transsulfuration enzyme cystathione β-synthetase (CBS). CBS silencing (shCBS) made BLBC cells less invasive, proliferate slower, more vulnerable to oxidative stress and cystine (CySSCy) deprivation, prone to ferroptosis, and less responsive to HIF1-α activation under hypoxia. shCBS xenograft tumors grew slower than controls and exhibited impaired angiogenesis and larger necrotic areas. Sulfur metabolite profiling suggested that realigned sulfide/persulfide- inducing functions of CBS are important in BLBC tumor progression. Supporting this, the exclusion of serine, a substrate of CBS for producing Cys but not for producing sulfide/persulfide, did not exacerbate CySSCy deprivation-induced ferroptosis in shCBS BLBC cells. Impaired Tyr phosphorylation was detected in shCBS cells and xenografts, likely due to persulfidation-inhibited phosphatase functions. Overexpression of cystathione γ-lyase (CSE), which can also contribute to cellular sulfide/persulfide production, compensated for the loss of CBS activities, and treatment of shCBS xenografts with a CSE inhibitor further blocked tumor growth. Glutathione and protein-Cys levels were not diminished in shCBS cells or xenografts, but levels of Cys persulfidation and the persulfide-catabolizing enzyme ETHE1 were suppressed. Finally, expression of enzymes of the oxidizing Cys catabolism pathway was diminished, but expression of the persulfideproducing CARS2 was elevated in human BLBC tumors. Hence, the persulfide-producing pathways are major targetable determinants of BLBC pathology that could be therapeutically exploited.

Original languageEnglish
Article numbere2100050118
JournalProceedings of the National Academy of Sciences of the United States of America
Volume118
Issue number45
DOIs
Publication statusPublished - 2021 Nov 9

Keywords

  • Basal-like breast cancer
  • Cystathione β-synthetase
  • Hydrogen sulfide
  • Persulfide
  • Transsulfuration

ASJC Scopus subject areas

  • General

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