To gain further molecular insights, we demonstrated that BRAF/MAPK pathway-phosphorylated FOS plays a critical role in this process by acting as a transcriptional factor of the GABPB gene. As an initial approach to exploring how BRAF V600E regulated GABPB, we performed an in silico analysis, which revealed that both MYC and FOS could bind to the 5′-UTR region of GABPB. Our actual experimental test demonstrated that FOS, but not MYC, could bind to the 5′-UTR of GABPB and activate its expression. We further demonstrated that BRAF V600E/MAPK pathway promoted the phosphorylation of FOS and its binding to the 5′-UTR of GABPB, robustly activating GABPB and the mutant TERT. To directly test if FOS phosphorylation was required for this function of FOS, we engineered FOS to alter the phosphorylation state of FOS and subsequently examined its function in the regulation of GABP and TERT. Compared with the wild-type FOS, phosphorylation-defective FOS lost the ability to activate GABPB and mutant TERT in cancer cells, providing direct evidence that phosphorylation of FOS is required for its regulation of GABPB and mutant TERT. These findings are consistent with the notion that MAPK/ERK pathway-mediated phosphorylation of FOS is required for its transcriptional activity and transformation efficiency36–38,40. The upregulated GABP transcriptional machinery by the BRAF V600E/MAPK pathway mediated by FOS is expected to promote TERT promoter mutation-dependent TERT expression by facilitating the recruitment and action of classical RNA polymerase. Indeed, this speculation is consistent with a recent study in which RNA polymerase II was found to be recruited to the mutant TERT promoter in response to the stimulation by the MAPK pathway41. Interestingly, a recent study showed that GABPA bound to the mutant TERT promoter mediated long-range chromatin interaction and enrichment of active histone marks as a component of the regulatory machinery for TERT transcription35.