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New research performed at Massachusetts General Hospital demonstrates that SIRT6 deficiency is a driving force in cancer progression.

SIRT6 Deficiency: A Driving Force in Cancer Progression

01/Dec/2013

Among the characteristics that cells acquire to initiate and sustain a tumor is their ability to adapt metabolically by switching from cellular respiration to aerobic glycolysis. New research at Massachusetts General Hospital, led by Raul Mostoslavsky, MD, PhD, demonstrates that the SIRT6 enzyme functions as a tumor suppressor by blocking this metabolic switch to glycolysis. Moreover, SIRT6 deficiency is an early event in tumorigenesis and a driving force in cancer progression, independent of oncogenic activation. The research was reported in the Dec. 7, 2012 issue of Cell. 1

The Cancer Metabolism Hypothesis

Research on cancer cell metabolism began in the 1920s, when German physician Otto Warburg showed that cancer cells switch from metabolizing glucose via cellular respiration to aerobic glycolysis. During the last seven years, evidence has mounted to suggest that metabolic changes play a significant role in tumor development and maintenance. Specifically, aerobic glycolysis provides the intermediate metabolites to sustain cell duplication and growth in rapidly proliferating cells.

The question remained whether the metabolic changes depend on the activity of oncogenes. Is the metabolic shift a consequence or a cause of tumorigenesis?

SIRT6, A Metabolic Switch

Dr. Mostoslavsky sought to disentangle cause from effect by investigating sirtuins, a family of protein deacetylases with roles in metabolism, life span and cancer. In a 2010 paper in Cell, his group demonstrated that SIRT6 controls expression of glycolytic genes acting as a histone deacetylase. SIRT6 deficiency caused increased glucose uptake and glycolysis in multiple cell types, even under normoxia. This helped explain his 2006 finding in Cell that mice born with SIRT6 deficiency die of hypoglycemia as a result of up-regulated aerobic glycolysis. Those results led him to hypothesize that SIRT6 may function as a tumor suppressor and that its loss might initiate cancer.

SIRT6 Deficiency Can Initiate Tumors

Working with mouse embryonic fibroblasts, he found that suppressing SIRT6 expression causes rapid proliferation and tumor formation without oncogene activation. Re-expression of SIRT6 reverses tumorigenesis and reduces glycolysis. Also, SIRT6 regulates cell proliferation by co-repressing the transcriptional activity of Myc, the global regulator of ribosome synthesis, which is required for protein synthesis. The researchers determined that ribosomal genes are up-regulated in SIRT6-deficient cells.

In analyzing human cancer databases, the researchers found that many cancers display reduced SIRT6 expression. Gene analysis of patient tissue samples collected by collaborators at the University of Glasgow over 11 years indicate that SIRT6 down-regulation is an early event and persists into later stages. Also, low SIRT6 levels in these samples correlate with shorter disease-free survival.

To investigate whether SIRT6 functions as a tumor suppressor in vivo, the Mass General researchers used conditional gene targeting to inactivate SIRT6 specifically in intestinal tissue of mouse models of colon carcinoma (with Apc activity). Apcmin/Sirt6-knockout mice developed triple the number of colorectal adenomas that control Apcmin mice had. The polyps were larger and higher grade and developed into more invasive tumors. Therefore, as observed retrospectively in human tumor samples, it appears that the SIRT6 loss contributes to both tumor development and tumor progression in vivo.

Inhibiting the glycolytic enzyme PDK1 with either RNA interference or the chemical dichloracetate inhibited glycolysis and almost completely abolished tumor formation in the SIRT6 knockout mice, while showing minimal effects in the controls.

Also, ribosomal gene expression was up-regulated in the SIRT6 knockout mice, as was glycolysis.

Thus, SIRT6-deficient tumors in mice had more proliferative capacity and were more aggressive than tumors with sufficient SIRT6 activity. But treating these mice with a glycolytic inhibitor shrank the tumors, without the need to reactivate SIRT6.

Future Directions

With this research bolstering the hypothesis that glycolytic enzymes are important targets for cancer therapies, Dr. Mostoslavsky is investigating how general the SIRT6-deficiency-driven metabolic changes are in cancer, and which tumor types will be susceptible to glycolytic inhibition. “Many glycolytic inhibitors are in the drug development pipeline, and they will likely be part of a multipronged approach to cancer therapy,” he predicts. Meanwhile, he believes that measuring SIRT6 expression levels in patient tumors can serve as a valuable biomarker in cancer diagnosis and in predicting tumor progression and response to therapy—all part of the tool kit for personalized cancer medicine.

Contributor

Raul Mostoslavsky, MD, PhD

  • Assistant Geneticist, Massachusetts General Hospital
  • Associate Professor, Harvard Medical School

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