A CTCF-LDHB axis converts nuclear lactate availability into an H3K18 acylation switch that directs alternative splicing in hypoxic breast cancer

Kakani, P.; Brahma, A.; Jithin, B.; Peter, R. M.; Panda, A.; Bansal, A.; Kumar, O. P.; Niyati, K.; Sahu, A.; Samaiya, A.; Shukla, S.

doi:10.64898/2026.10.27.762200

bioRxiv · 10.64898/2026.10.27.762200

A CTCF-LDHB axis converts nuclear lactate availability into an H3K18 acylation switch that directs alternative splicing in hypoxic breast cancer

Kakani, P.·Brahma, A.·Jithin, B.·Peter, R. M.·Panda, A.·Bansal, A.·Kumar, O. P.·Niyati, K.·Sahu, A.·Samaiya, A.·Shukla, S.

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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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Kakani, P., Brahma, A., Jithin, B., Peter, R. M., Panda, A., Bansal, A., Kumar, O. P., Niyati, K., Sahu, A., Samaiya, A., Shukla, S.. 2026-10-29. A CTCF-LDHB axis converts nuclear lactate availability into an H3K18 acylation switch that directs alternative splicing in hypoxic breast cancer. https://doi.org/10.64898/2026.10.27.762200

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