Gatekeeping Growth: How Tumour Suppressors Restrain Acetyl-CoA Flux to Limit Cancer Stem Cell Self-Renewal

AbstractHistone acetylation requires acetyl coenzyme A (acetyl-CoA) as its obligate acetyl donor, which meanschromatin accessibility is mechanistically tied to a cell's metabolic state rather than being anindependent layer of regulation. This review traces how that coupling is exploited by cancer stem cells(CSCs) to sustain self-renewal gene programs, and how two classical tumour suppressors intervene torestrain it. Starting from the foundational discovery that ATP-citrate lyase (ACLY) links glucosemetabolism to histone acetylation in mammalian cells, and its parallel role in maintaining pluripotency inembryonic stem cells, the paper traces how cancer cells appear to co-opt the same logic: hypoxia-drivenmetabolic rewiring and receptor-AKT signalling both converge on ACLY- and ACSSdependent acetyl-CoAproduction to sustain histone acetylation at stemness-associated loci. It then examines two points wheretumour suppressors intervene in this exact axis — SIRT6, which restrains nuclear ACLY abundance, andp53, whose own transcriptional activation is itself acetylation-dependent — before considering a findingthat complicates the picture: ACLY loss can trigger p53 activation through a route that has nothing to dowith acetyl-CoA at all. The paper argues that metabolism and tumour suppression form a genuine twoway loop here, not a one-directional pipeline, and closes by weighing the therapeutic promise and risk oftargeting this axis directly.