Our work reveals that SPTBN1 functions to control the stability of the p65 subunit of the NF-κB superfamily through collaboration of the suppressor of cytokine signaling 1 (SOCS1) protein, an E3 ligase of p65, and that this novel regulatory cascade might be an important molecular mechanism underlying the loss of tumor suppressive function of SPTBN1 during cancer development and progression. Here, SPTBN1 is linked to neoplasm.