Targeting Serine Hydroxymethyltransferase 2 (Shmt2) Suppresses Hepatocarcinoma

Glycolytic intermediate 3-phosphoglycerate branched from glycolysis pathway to fuel serine-glycine biosynthesis pathway. Several studies have shown that glycine consumption is strongly correlated to the proliferation rate of cancer cells. Therefore targeting serine-glycine biosynthesis pathway is a promising strategy due to the fact that many of its genes are up-regulated in cancer cells. These genes include PHGDH, PSAT1 and GLDC. Here, we demonstrate that targeting serine hydroxymethyltransferase 2 (SHMT2), also a member of serine-glycine biosynthesis pathway, is able to suppress hepatocarcinoma both in vitro and in vivo. SHMT2 simultaneously converts serine to glycine and tetrahydrofolate to 5,10-methylenetetrahydrofolate. We found that this gene is up-regulated in Hep3B, HepG2 and Huh-7 liver cancer cells versus THLE2 normal liver cells. Knockdown of SHMT2 effectively suppressed Huh-7 cell growth and tumorigenicity. No tumor was formed after inoculation of SHMT2-knockdown Huh-7 cells in nude mice as compared to 100% tumor formation with control Huh-7 cells. The data from tetracycline-inducible SHMT2-knockdown xenograft mouse model showed that SHMT2 inhibition could reduce tumor growth and tumor incidence as well as delayed tumor onset. We also found that SHMT2-knockdown Huh-7 cells were more vulnerable to the cytotoxicity of doxorubicin, a conventional chemotherapeutic agent, as compared to the control Huh-7 cells. On the other hand, overexpression of SHMT2, however, could not transform THLE2 cells into malignancy suggesting that SHMT2 might not a key driver in liver tumorigenesis. SHMT2 activity is correlated to cancer phenotype as shown by the NMR data via metabolic tracing with 13C-glycine. Supplementation of glycine, rather than 5,10-methylenetetrahydrofolate, could reverse the reduced tumorigenicity caused by SHMT2-knockdown. Taken together, our data support that SHMT2 is a potential target in the treatment of hepatocarcinoma. Citation Format: Chern Chiuh Woo, Way Cherng Chen, Teck Hock Philip Lee. Targeting serine hydroxymethyltransferase 2 (SHMT2) suppresses hepatocarcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1060.