Targeting condensin, a vital spot of MYCN-amplified neuroblastoma

Neuroblastoma is a disease in which malignant cells form in nerve tissue. Amplification of MYCN, a member of the MYC proto-oncogene family, is frequently observed in neuroblastoma, and it is associated with malignant phenotype and poor prognosis.¹ In the April 1, 2014 issue of Cell Cycle, Murakami-Tonami et al.² reported that downregulation of SMC2, a subunit of condensin, leads to cell death through dysfunction of DNA repair specifically in MYCN-amplified neuroblastoma cells, suggesting that SMC2 can be an effective anti-cancer target in this type of tumor.

There are 2 types of condensin in human cells, namely condensin I and condensin II.³ SMC2 and SMC4 are common subunits of both types of condensin. In addition, condensin I contains CAP-D2, CAP-H, and CAP-G, and condensin II contains CAP-D3, CAP-H2, and CAP-G2. From the analysis of the expression profile in MYCN-amplified neuroblastoma cells and transgenic mouse model, the authors found the correlation between amplification of MYCN and elevated expression of SMC2. The observed correlation was supported by the finding that N-MYC binds to E-box, a consensus MYC-binding sequence for transcriptional activation located within the intron of SMC2. Interestingly, amplification of MYCN and depletion of SMC2 leads to a synergistic lethal effect characterized by induction of apoptosis through accumulation of DNA damage. Because amplification of MYC induces DNA damage by producing relative oxygen species (ROS) or replicative stress,^4,5 the authors explored the functional link between condensin and DNA damage response (DDR). Intriguingly, they found that depletion of SMC2 leads to downregulation of DDR genes, including BRCA1, MRE11, NBS1, RAD50, and, ATM.⁶ These data explain why depletion of SMC2 leads to higher sensitivity to DNA damage, especially in MYCN-amplified neuroblastoma cells. They also show that SMC2 interacts with MYCN, and they bind to E-box within at least NBS1 intron, suggesting the possibility that SMC2 cooperates with MYCN for activating DDR genes. Upregulation of SMC4 and CAP-D2 (condensin I subunit), but not condensin II subunit, are correlated with poor prognosis in neuroblastoma with high expression of MYCN, suggesting that condensin I complex cooperates with MYCN.

Accordingly, this study suggests that targeting condensin in MYCN-driven neuroblastoma might promote tumor-specific retardation in cell growth and, therefore, have a therapeutic impact. If amplification of other MYC family genes, such as c-MYC and MYCL, causes synergetic defects with SMC2-depletion, such “condensin-targeting” strategy might be applicable to other types of tumors.

Murakami-Tonami Y, et al. Cell Cycle. 2014;13:1115–31. doi: 10.4161/cc.27983.