In cancer cells, Ca²⁺-activated K⁺ channels K_Ca1.1 and K_Ca3.1 are co-localized with Ca²⁺-permeable Orai/TRP channels to provide a positive-feedback loop for Ca²⁺ entry. They are responsible for the promotion of cell growth and metastasis in the different types of cancer, and are therefore potential therapeutic targets and biomarkers for cancer. We determined the epigenetic and post-transcriptional dysregulation of K_Ca3.1 by class I histone deacetylase (HDAC) inhibitors in breast and prostate cancer cells. We further determined the transcriptional repression and protein degradation of K_Ca1.1 by vitamin D receptor (VDR) agonists and androgen receptor (AR) antagonists, which are expected as potential therapeutic drugs for triple-negative breast cancer. A class III HDAC, SIRT1 is involved in cancer growth, stemness, and metastasis. We here introduce SIRT1-mediated regulation of K_Ca3.1 expression in breast, prostate, and colorectal cancer by three-dimensional spheroid culture. The anti-inflammatory cytokine, interleukin-10 (IL-10) is an immunosuppressive factor involved in tumorigenesis, and plays a crucial role in escape from tumor immune surveillance. We determined K_Ca3.1 activators are a possible therapeutic option to suppress the tumor-promoting activities of IL-10. These results may provide new insights into cancer treatment focused on Ca²⁺-activated K⁺ channels.