Oncotarget

Research Papers:

Downregulating serine hydroxymethyltransferase 2 (SHMT2) suppresses tumorigenesis in human hepatocellular carcinoma

Chern Chiuh Woo, Way Cherng Chen, Xing Qi Teo, George K. Radda and Philip Teck Hock Lee _

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Oncotarget. 2016; 7:53005-53017. https://doi.org/10.18632/oncotarget.10415

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Abstract

Chern Chiuh Woo1, Way Cherng Chen1, Xing Qi Teo1, George K. Radda1, Philip Teck Hock Lee1

1Singapore Bioimaging Consortium, Singapore

Correspondence to:

Philip Teck Hock Lee, email: philip_lee@sbic.a-star.edu.sg

Keywords: SHMT2, hepatocellular carcinoma, serine, glycine, 5,10-methylenetetrahydrofolate

Received: January 25, 2016     Accepted: June 29, 2016     Published: July 06, 2016

ABSTRACT

Serine-glycine biosynthetic pathway diverts the glycolytic intermediate 3-phosphoglycerate to synthesize serine and glycine, of which the latter was found to correlate with cancer cell proliferation. Increased de novo biosynthesis of glycine by serine hydroxymethyltransferase 2 (SHMT2) is the central mechanism to fuel one-carbon pools supporting tumorigenesis. However, the therapeutic potential in targeting SHMT2 in hepatocellular carcinoma (HCC) is unknown. In this study we showed that SHMT2 inhibition significantly suppressed liver tumorigenesis. In vitro, SHMT2-knockdown was found to reduce cell growth and tumorigenicity in Huh-7 and HepG2 liver cancer cells. Moreover SHMT2-knockdown Huh-7 cells failed to form tumor xenograft after subcutaneous inoculation into nude mice. Similarly, inducible SHMT2 inhibition, via doxycycline-added drinking water, was found to reduce tumor incidence and tumor growth in a human tumor xenograft mouse model. SHMT2-knockdown increased the susceptibility of Huh-7 cells to doxorubicin suggesting its potential in combination chemotherapy. Through isotopomer tracing of [2–13C] glycine metabolism, we demonstrated that SHMT2 activity is associated with cancer phenotype. However, overexpression of SHMT2 was insufficient to transform immortalized hepatic cells to malignancy, suggesting that SHMT2 is one of the building blocks in liver cancer metabolism but does not initiate malignant transformation. Moreover, our results suggest that glycine, but not 5,10-methylenetetrahydrofolate, from the SHMT2-mediated enzymatic reaction is instrumental in tumorigenesis. Indeed, we found that SHMT2-knockdown cells exhibited increased glycine uptake. Taken together, our data suggest that SHMT2 may be a potential target in the treatment of human HCC.


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