Wen Pan and colleagues have demonstrated that CSBF/C10orf99 inhibits colon cancer cell growth through inducing G1 arrest as a novel potential cytokine.
Cytokines are usually small secreted proteins with optimal activity at quite low concentrations and their functions are dependent on the binding of specific receptors. In the present study, they identified a novel potential cytokine CSBF/C10orf99 using immunogenomics. CSBF/C10orf99 is a classical secreted protein with a regular N-terminal signal peptide of 24 amino acids. SUSD2 is indispensable for the growth inhibitory effect of CSBF/C10orf99 on colon cancer cells and recombinant sSUSD2-Fc can block its function. CSBF/C10orf99 displays a bell-shaped activity curve and its optimal effect is about 10 ng/ml, which is in accordance with the characteristics of cytokines.
To our knowledge, this is the first systemic study of CSBF/C10orf99. The expressional and functional characteristics of CSBF/C10orf99 indicate it may be a tumor suppressor. Its gene is located on chromosome 10q23.1 beside the genomic region of tumor suppressor PTEN (10q23.3). Inactivation of TSGs through promoter methylation, gene mutation, or loss of heterozygosity is important for carcinogenesis. In human colon cancer cell lines, the expression of CSBF/C10orf99 cannot be restored by Aza or combined with TSA, which indicates that it is not regulated by promoter methylation. The mechanism underlying the down-regulation of CSBF/C10orf99 remains to be studied further. Possible roles for genetic and/or other epigenetic controls must be considered. The promoter of SUSD2 contains non-typical CpG islands, but it can be restored by Aza or combined with TSA, indicating that promoter methylation manipulates its expression directly or transcription factors regulating its expression are epigenetically regulated.
Intriguingly, higher expression of CSBF/C10orf99 and SUSD2 has also been detected in a few colon cancer samples (7/42 and 4/42), which is similar to the increased expression of tumor suppressor p16 in many malignant tumors. There are some possible mechanisms to elucidate why p16 overexpression occurs. On one hand, partial loss of p16 function due to missense mutations can be compensated by elevated expression as observed in some tumor specimens. On the other hand, in the presence of wild-type p16, other molecular events, such as over-expression of CDC6 and cyclin D1, or deregulation of Rb in tumor cells and cancer tissues have the potential to positively feedback p16 expression. Given these available mechanisms and our results, there might be some mutations of CSBF/C10orf99 and SUSD2, or other downstream molecules changing in the mentioned samples.
This study shows that CSBF/C10orf99 inhibits G1-S phase transition through down-regulating cyclin D and CDK6. G1-S phase transition is known to be a major checkpoint for cell cycle progression. It is necessary to identify the intracellular interacting proteins of SUSD2 and elucidate its mechanism on the modulation of cyclin D and CDK6 in the future study, which will be helpful to understand the pathogenesis of colon cancer.
Reference
Wen Pan, Yingying Cheng,etc. CSBF/C10orf99, a novel potential cytokine, inhibits colon cancer cell growth through inducing G1 arrest, Scientific Reports, 4, Article number: 6812 ︳doi:10.1038/srep06812