KCTD6 functions as a substrate-specific adapter protein for BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein ligase complexes, mediating the ubiquitination and proteasomal degradation of target proteins 1. The protein specifically regulates turnover of muscle small ankyrin-1 isoform 5 (sAnk1.5) through cullin-3-dependent mechanisms, with this process modulated by posttranslational modifications including neddylation, ubiquitination, and acetylation 1. KCTD6 promotes ubiquitination of HDAC1 in an oligomerization-dependent manner with KCTD11, functioning as a tumor suppressor by antagonizing the Hedgehog signaling pathway 2. By degrading HDAC1, KCTD6 maintains GLI1 in an acetylated, transcriptionally inactive state, thereby inhibiting medulloblastoma cell growth and tumorigenicity 2. The protein demonstrates high-affinity binding to Cullin 3 through its BTB domain, forming stable 4:4 stoichiometric complexes 3. KCTD6 interacts with the deubiquitylase USP21 and is involved in Gli1 regulation at the centrosome 4. Additionally, KCTD6 has been implicated in keratinocyte differentiation regulation and identified as a potential biomarker in kidney transplant rejection 56.