Cancer cells have an increased demand for building materials and energy. They meet these added demands by altering their metabolism, e.g., taking in larger amounts of fuel.
Historically, these metabolic changes have been considered a consequence rather than a cause of cancer, and therefore not good drug targets. Now, a new study in Nature Cancer—“The serine hydroxymethyltransferase-2 (SHMT2) initiates lymphoma development through epigenetic tumor suppressor silencing”—from the Sloan Kettering Institute laboratory of Hans-Guido Wendel, MD, challenges that assumption.
“Cancer cells adapt their metabolic activities to support growth and proliferation. However, increased activity of metabolic enzymes is not usually considered an initiating event in the malignant process. Here, we investigate the possible role of the enzyme serine hydroxymethyltransferase-2 (SHMT2) in lymphoma initiation. SHMT2 localizes to the most frequent region of copy number gains at chromosome 12q14.1 in lymphoma. Elevated expression of SHMT2 cooperates with BCL2 in lymphoma development; loss or inhibition of SHMT2 impairs lymphoma cell survival,” write the investigators.
“SHMT2 catalyzes the conversion of serine to glycine and produces an activated one-carbon unit that can be used to support S-adenosyl methionine synthesis. SHMT2 induces changes in DNA and histone methylation patterns leading to promoter silencing of previously uncharacterized mutational genes, such as SASH1 and PTPRM. Together, our findings reveal that amplification of SHMT2 in cooperation with BCL2 is sufficient in the initiation of lymphomagenesis through epigenetic tumor suppressor silencing.”
“We find that increased activity of a normal metabolic enzyme, called SHMT2, is sufficient to transform normal B cells into B cell lymphomas,” says Sara Parsa, PhD, a postdoctoral fellow in the Wendel lab and the first author of the paper.
SHMT2’s main role is to speed the conversion of serine into glycine, simultaneously generating a methyl group. This methyl group, the researchers found, epigenetically binds to the promoter of genes that encode previously unrecognized tumor suppressor proteins. This binding turns off these tumor suppressors, resulting in B cell lymphoma.
SHMT2 sits on a region of chromosome 12 that is often amplified in B cell lymphoma. The increased number of gene copies leads to more of the enzyme being made. In animals, this is enough to cause lymphomas.
Other cancer cells, the researchers note, also carry the same gene amplification and contain abundant SHMT2, revealing this to be a common theme that could be exploited therapeutically.
While scientists have documented previous links between metabolism and cancer, most of these involve metabolic proteins that are mutated. “This may be the first time that anyone has shown that too much of a normal metabolic enzyme can drive cancer,” Wendel says. “It reinforces the idea that metabolic changes can be a cause rather than simply an effect of cancer.”
He notes that the research reveals that SHMT2 could be a potential drug target for cancer therapies, provided there is a way to target it specifically in cancer cells.
