Editors' ChoiceCancer

SAMpling cancer development one carbon at a time

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Science Translational Medicine  20 Mar 2019:
Vol. 11, Issue 484, eaax2731
DOI: 10.1126/scitranslmed.aax2731

Abstract

PKCλ/ι depletion promotes metabolic reprogramming during neuroendocrine prostate cancer differentiation by increasing DNA methylation.

Prostate cancer is the most common noncutaneous cancer in American men but is cured in the vast majority of patients by surgery or radiation. The molecular driver of prostate cancer is the androgen receptor, a transcription factor which functions when bound to testosterone. In about 20% of patients, prostate cancer recurs after initial treatment, and these tumors initially respond well to hormonal therapies that target the androgen receptor. Over time, however, stronger hormonal therapy results in a lethal variant of prostate cancer that exhibits resistance to androgen receptor–directed treatment by undergoing neuroendocrine differentiation. Efforts over the last several years have focused on studying epigenetic regulation of neuroendocrine prostate cancer (NEPC) development, which includes differential DNA methylation of genes regulating stemness. In a recent report, Reina-Campos et al. find that prostate cancer accomplishes this neuroendocrine reprogramming by downregulating protein kinase C (PKC)λ/ι.

The family of PKC serine/threonine protein kinases play important roles in multiple signal transduction cascades. Recent pan-cancer analyses have reported that all PKC isoforms are inactivated in most cancers, suggesting that they are tumor suppressors. In this study, the investigators also observed that PKCλ/ι expression is suppressed in multiple independent datasets of patients with advanced prostate cancer, consistent with its role as a tumor suppressor in prostate cancer. Using both cell lines and mouse models, the authors showed that the loss of PKCλ/ι drives NEPC differentiation. In these models, PKCλ/ι depletion also resulted in upregulation of genes involved in the serine, glycine, one-carbon pathway (SGOCP).

SGOCP activity produces S-adenosylmethionine (SAM), which a one-carbon source of methyl groups that are used for DNA methylation. DNA methyltransferases (DNMTs) catalyze this reaction, and all DNMTs require SAM for their activity. Therefore, this finding of increased SGOCP activity suggested that NEPC differentiation is fueled by PKCλ/ι loss resulting from changes in DNA methylation. The authors then showed that inhibiting DNMT activity was sufficient to reduce NEPC differentiation in PKCλ/ι-depleted xenografts.

These results suggest that inhibitors of DNMTs, such as decitabine and azacytidine, may be attractive potential therapies for patients with NEPC accompanied by PKCλ/ι loss. These chemotherapies are already approved by the FDA for treatment of myelodysplastic syndrome and can therefore be used in patients. Future clinical trials will be needed to assess whether DNMT-directed therapies will prevent the development of NEPC in patients with PKCλ/ι-suppressed prostate cancers and thus whether these drugs could offer a much-needed option for the lethal neuroendocrine variant of prostate cancer.

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