A CTCF-LDHB axis converts nuclear lactate availability into an H3K18 acylation switch that directs alternative splicing in hypoxic breast cancer
- 1Department of Biological Sciences, Indian Institute of Science Education and Research Bhopal, Madhya Pradesh 462066, India.
Abstract
Lactate accumulating in hypoxic tumours lactylates histones, coupling metabolic state to chromatin. Why it differs between tumours of comparable glycolytic rate has remained unresolved. Here we show that nuclear, rather than total intracellular, lactate availability determines histone H3K18 lactylation in breast cancer, and that CCCTC-binding factor (CTCF) and lactate dehydrogenase B (LDHB) jointly set it. CTCF sustains glycolytic gene expression under hypoxia and drives LDHB in triple-negative breast cancer (TNBC), whereas a CTCF-ER complex represses LDHB in non-TNBC. LDHB consumes lactate favouring H3K18 acetylation; where LDHB is low, CTCF-dependent MCT1 delivers lactate into the nucleus and sustains lactylation. At a CTCF site downstream of TACC3 exon 3, an invariant polymerase II pause couples kinetic and adaptor control of splicing, with the mark deciding the outcome: H3K18la recruits SMARCA4 and hnRNPA1 to skip the exon, generating an isoform that drives EMT, whereas H3K18ac recruits TRIM33 and SRSF10 to include it, generating one that confers stemness. Inhibiting LDHB restores exon skipping and suppresses tumour growth in vivo. Nuclear lactate availability therefore acts as a metabolic switch that converts hypoxic stress into subtype-specific splicing decisions and identifies LDHB as a tractable target in TNBC.
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BibTeX
@misc{kakani2026ctcfldhb,
title = {{A CTCF-LDHB axis converts nuclear lactate availability into an H3K18 acylation switch that directs alternative splicing in hypoxic breast cancer}},
author = {P. Kakani and A. Brahma and B. Jithin and R. M. Peter and A. Panda and A. Bansal and O. P. Kumar and K. Niyati and A. Sahu and A. Samaiya and S. Shukla},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.27.762200},
url = {https://www.biorxiv.org/content/10.64898/2026.10.27.762200v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - A CTCF-LDHB axis converts nuclear lactate availability into an H3K18 acylation switch that directs alternative splicing in hypoxic breast cancer
AU - P. Kakani
AU - A. Brahma
AU - B. Jithin
AU - R. M. Peter
AU - A. Panda
AU - A. Bansal
AU - O. P. Kumar
AU - K. Niyati
AU - A. Sahu
AU - A. Samaiya
AU - S. Shukla
PY - 2026
DA - 2026/10/27
PB - bioRxiv
DO - 10.64898/2026.10.27.762200
UR - https://www.biorxiv.org/content/10.64898/2026.10.27.762200v1
AB - Lactate accumulating in hypoxic tumours lactylates histones, coupling metabolic state to chromatin. Why it differs between tumours of comparable glycolytic rate has remained unresolved. Here we show that nuclear, rather than total intracellular, lactate availability determines histone H3K18 lactylation in breast cancer, and that CCCTC-binding factor (CTCF) and lactate dehydrogenase B (LDHB) jointly set it. CTCF sustains glycolytic gene expression under hypoxia and drives LDHB in triple-negative breast cancer (TNBC), whereas a CTCF-ER complex represses LDHB in non-TNBC. LDHB consumes lactate favouring H3K18 acetylation; where LDHB is low, CTCF-dependent MCT1 delivers lactate into the nucleus and sustains lactylation. At a CTCF site downstream of TACC3 exon 3, an invariant polymerase II pause couples kinetic and adaptor control of splicing, with the mark deciding the outcome: H3K18la recruits SMARCA4 and hnRNPA1 to skip the exon, generating an isoform that drives EMT, whereas H3K18ac recruits TRIM33 and SRSF10 to include it, generating one that confers stemness. Inhibiting LDHB restores exon skipping and suppresses tumour growth in vivo. Nuclear lactate availability therefore acts as a metabolic switch that converts hypoxic stress into subtype-specific splicing decisions and identifies LDHB as a tractable target in TNBC.
ER -