Acetyl-CoA synthetase 2 inhibition sensitizes cells to metabolic stress and DNA damage

Dysregulation of DNA damage response (DDR) is a common feature in cancer, which impairs cellular sensitivity to DNA damaging drugs. Targeting DDR regulators is therefore an attractive strategy to improve response to DNA damaging agents. Histone modifications regulate the DDR by effecting the accessibility of DDR proteins to chromatin. The nuclear-cytosolic enzyme, acetyl-CoA Synthetase 2 (ACSS2), that synthesizes acetyl CoA from acetate is involved in histone acetylation and fatty acids synthesis. As acetyl-CoA is a key metabolic intermediate, disrupting acetyl-CoA homeostasis can also influence cancer cell survival during metabolic stress, such as hypoxia. We therefore studied the potential of targeting ACSS2 to sensitize cells to DDA.

Pancreatic ductal adenocarcinoma (PDAC) and breast carcinoma cell lines were incubated with ACSS2 inhibitor (ACSS2i) under hypoxia and normoxia. Incorporation of ¹³C labeled acetate into acetyl CoA and fatty acids was measured by mass spectrometric analysis and incorporation of ¹⁴C labeled acetate into fatty acids and histones was measured by radioactive assay. ACSS2 inhibition lead to a decrease in both fatty acid synthesis and histone acetylation, ACSS2 activity was further inhibited under hypoxia. In all cell lines, ACSS2 inhibition decreased cell proliferation and increased cell death, these effects were enhanced under hypoxia. ACSS2 inhibition sensitized cells to cisplatin, or to ionizing radiation. Cell sensitization to DNA damage was further aggravated under hypoxia.

Our results demonstrate that ACSS2 inhibition increases sensitivity to ionizing radiation and chemotherapeutic agents and may provide a new modality of anti-cancer treatment through attacking metabolic vulnerabilities.