All the findings provide the mechanistic insights into the expression regulation of hTERT in CRC initiation and development, demonstrate that disrupting the SPT6/SND1 transcriptional activation axis might be a compelling strategy to target hTERT‐dependent cancer, especially CRC, and also prompt the application of multiple inhibitors, respectively, against SPT6, SND1, and hTERT for optimal anticancer effects. The gene discussed is SUPT6H; the disease is colorectal carcinoma.