Rewiring of Lactate–Interleukin-1 β Autoregulatory Loop with Clock-Bmal1: a Feed-Forward Circuit in Glioma

A desynchronized circadian rhythm in tumors is associated with aberrant inflammation and dysregulated metabolism.

• The tumor metabolite lactate increases the proinflammatory cytokine interleukin-1β (IL-1β) alongside elevated levels of core circadian regulators Clock and Bmal1.
• Decreasing Bmal1 and Clock levels through small interfering RNA (siRNA) reduces lactate dehydrogenase A (LDHA) and IL-1β levels, as well as the release of lactate and proinflammatory cytokines.
• Lactate facilitates the modification of Bmal1, which interacts with Clock to regulate IL-1β levels and is influenced by IL-1β in return.
• Functional E-box sites on LDHA and IL-1β promoters were confirmed to play a role in their regulation by Clock and Bmal1.
• The lactate-IL-1β interaction enhances the recruitment of Clock-Bmal1 to E-box sites, leading to changes in histone modifications and RNA polymerase II activity.
• Data analysis suggests that the lactate-IL-1β cross talk may also be present in other cancers and correlates with patient survival and drug sensitivity.

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