C1orf35 contributes to tumorigenesis by activating c-MYC transcription in multiple myeloma.

Multiple myeloma (MM) is a clinically and biologically heterogenous event that accounts for approximately 10% of all hematological malignancies. Chromosome 1 open reading frame 35 (C1orf35) is a gene cloned and identified in our laboratory from a MM cell line (GenBank: AY137773), but little is known about its function. In the current study, we have confirmed that C1orf35 is a candidate oncogene, and it can promote cell cycle progression from G1 to S. Later, we found that C1orf35 is able to affect the cell proliferation by modulating the expression of c-MYC (v-myc myelocytomatosis viral oncogene homolog), and the oncogenic property of C1orf35 can be rescued by c-MYC inhibition. Herein, we found positive association between C1orf35 and c-MYC in MM patients and in MM cell lines. The correlation analysis of the genes coamplified in MM patients from GEO datasets showed a correlation between C1orf35 and c-MYC, and the expression data of different stages of plasma cell neoplasm acquired from GEO datasets showed that the expression of C1orf35 increase with the progression of the disease. This indicates that C1orf35 may play a role in the disease progression. Moreover, C1orf35 can modulate c-MYC expression and rescue c-MYC transcription inhibited by Act D. Finally, we have shown that C1orf35 activates c-MYC transcription by binding to the i-motif of Nuclease hypersensitivity element III1 (NHE III1) in the c-MYC promoter. Not only does our current study advance our knowledge of the pathogenesis and therapeutic landscape of MM, but also of other cancer types and diseases that are initiated with deregulated c-MYC transcription.