Hypoxia upregulating ACSS2 enhances lipid metabolism reprogramming through HMGCS1 mediated PI3K/AKT/mTOR pathway to promote the progression of pancreatic neuroendocrine neoplasms.

Background: Pancreatic neuroendocrine neoplasms (pNENs) are relatively rare. Hypoxia and lipid metabolism-related gene acetyl-CoA synthetase 2 (ACSS2) is involved in tumor progression, but its role in pNENs is not revealed. This study showed that hypoxia can upregulate ACSS2, which plays an important role in the occurrence and development of pNENs through lipid metabolism reprogramming. However, the precise role and mechanisms of ACSS2 in pNENs remain unknown.

Methods: mRNA and protein levels of ACSS2 and 3-hydroxy-3-methylglutaryl-CoA synthase1 (HMGCS1) were detected using quantitative real-time PCR (qRT-PCR) and Western blotting (WB). The effects of ACSS2 and HMGCS1 on cell proliferation were examined using CCK-8, colony formation assay and EdU assay, and their effects on cell migration and invasion were examined using transwell assay. The interaction between ACSS2 and HMGCS1 was verified by Co-immunoprecipitation (Co-IP) experiments, and the functions of ACSS2 and HMGCS1 in vivo were determined by nude mouse xenografts.

Results: We demonstrated that hypoxia can upregulate ACSS2 while hypoxia also promoted the progression of pNENs. ACSS2 was significantly upregulated in pNENs, and overexpression of ACSS2 promoted the progression of pNENs and knockdown of ACSS2 and ACSS2 inhibitor (ACSS2i) treatment inhibited the progression of pNENs. ACSS2 regulated lipid reprogramming and the PI3K/AKT/mTOR pathway in pNENs, and ACSS2 regulated lipid metabolism reprogramming through the PI3K/AKT/mTOR pathway. Co-IP experiments indicated that HMGCS1 interacted with ACSS2 in pNENs. Overexpression of HMGCS1 can reverse the enhanced lipid metabolism reprogramming and tumor-promoting effects of knockdown of ACSS2. Moreover, overexpression of HMGCS1 reversed the inhibitory effect of knockdown of ACSS2 on the PI3K/AKT/mTOR pathway.

Conclusion: Our study revealed that hypoxia can upregulate the lipid metabolism-related gene ACSS2, which plays a tumorigenic effect by regulating lipid metabolism through activating the PI3K/AKT/mTOR pathway. In addition, HMGCS1 can reverse the oncogenic effects of ACSS2, providing a new option for therapeutic strategy.