Credit: CORBIS

The Myc family of transcription factors are well-known oncoproteins and three new studies contribute important insights into mechanisms of MYC regulation and the roles of MYCN in tumorigenesis and progression.

combined targeting of MYC and P-TEFb could be an effective therapeutic strategy in tumour cells that overexpress MYC.

Richard Young and colleagues demonstrate that MYC plays a key part in regulating transcriptional elongation by RNA polymerase II (Pol II). Previous studies suggested that MYC participates in positive elongation factor b (P-TEFb)-dependent release of paused Pol II, as MYC can bind P-TEFb and stimulate transcriptional elongation in cancer cells. Consistent with these findings, Young and co-workers found that MYC and its heterodimer partner MAX bind to P-TEFb in embryonic stem (ES) cells. To directly test whether MYC regulates pause release, they treated ES cells with an inhibitor of MYC–MAX dimerization, 10058-F4. This decreased the expression of most MYC target genes and decreased the levels of the Pol II form associated with elongation, but the levels of the form of Pol II associated with transcriptional initiation were unaffected. Moreover, reduction of MYC activity by 10058-F4 or by short hairpin RNA knockdown reduced the levels of Pol II across transcribed regions of MYC target genes, but had little effect on the levels of promoter-proximal Pol II. The authors suggest that combined targeting of MYC and P-TEFb could be an effective therapeutic strategy in tumour cells that overexpress MYC.

In a second paper, Matthew Freedman and colleagues provide new insights into the mechanism by which prostate, colon and breast cancer risk loci in the 8q24 gene desert likely act through MYC, which is located several hundred kilobases away from the 8q24 risk regions. The authors tested whether the 8q24 risk regions physically interacted with MYC in prostate (LNCaP), breast (MCF-7) and colon (LS174T) cancer cell lines. They found that each of the cancer risk regions robustly interacted with MYC in their respective tissue-specific cancer cell lines, but did not in non-matched cell lines so, for example, the breast cancer risk locus did not interact with MYC in the prostate cancer cell line. The authors suggest that the 8q24 risk loci can form tissue-specific long-range chromatin loops with MYC. As the risk loci have been previously shown to have epigenetic marks consistent with enhancers, they may affect MYC expression. However, the regulatory mechanism is unlikely to be clear cut as there is currently scant evidence for associations between risk allele status and MYC expression levels.

In a third paper, Louis Chesler, William Weiss and colleagues show that MYCN is a key player in multiple stages of medulloblastoma development. They profiled mRNA in human medulloblastomas and cerebella, and found that MYCN was expressed in most of the medulloblastomas and was expressed at high levels in fetal cerebella, but not in normal adult cerebella. Is misexpression of MYCN important for medulloblastoma development? To address this, the authors generated transgenic mice that specifically expressed human MYCN in the cerebellum under the control of the tetracycline-regulated gene expression system, allowing them to switch MYCN expression on and off using doxycycline. The mice developed medulloblastomas at high penetrance and recapitulated the human spectrum of medulloblastoma pathologies. In addition, there was rare metastatic spread, indicating MYCN also functions in tumour progression and metastasis. Downregulation of MYCN by doxycycline treatment at birth blocked tumour formation, supporting a role for MYCN in tumour initiation. Moreover, transient downregulation of MYCN in adult mice with established tumours led to clearance and senescence of tumour cells and improved survival, suggesting that continuous expression of MYCN is needed for tumour maintenance. Therefore, MYCN could be an important therapeutic target in medulloblastoma.