Alternative transcription start site selection in ACSS2 controls its nuclear localization and promotes ribosome biosynthesis in hepatocellular carcinoma.

Acetyl-CoA synthetase 2 (ACSS2) generates acetyl-CoA from acetate is important for histone acetylation and gene expression. ACSS2 fulfills distinct functions depending on its cellular location in tumor cells. The role and cellular localization of ACSS2 in hepatocellular carcinoma (HCC) remains to be studied. Herein, we identified that the alternative transcription start site selection of ACSS2 was significantly different between HCC and corresponding adjacent tissues. Alternative transcription start site selection produced two different ACSS2 transcripts, ACSS2-S1 and ACSS2-S2. The two isoforms of ACSS2 had different subcellular localization and different functions. Overexpression of ACSS2-S2 promoted cell proliferation and invasion, but ACSS2-S1 did not. The ACSS2-S1 was mainly present in cytoplasm, and ACSS2-S2 was distributed in both nucleus and cytoplasm. Finally, we demonstrated that alternative transcription start site selection of ACSS2 correlates ribosome biogenesis in HCC. Our findings reveal an oncogenic role of ACSS2-S2 in HCC progression via increase of ribosome biogenesis, and suggest ACSS2-S2 might be a potential therapeutic target against the HCC.