SET is a multifunctional protein that acts as an intrinsic inhibitor of the tumor suppressor protein phosphatase 2A and a histone chaperone. Increased SET levels have been observed in various cancers; however, the underlying molecular mechanisms remain unclear. We found that SET protein accumulates with the increasing density of cultured cells. In this study, we aimed to clarify the mechanism underlying the accumulation of SET.
High cell density increased the SET levels in all the adherent cells analyzed. This phenomenon was observed in both cancer cell lines and non-cancer cell lines. The mRNA levels of SET were not affected by cell density, while the half-life of SET was extended at high cell densities. Autophagy inhibition led to SET accumulation, indicating the involvement of autophagy. However, cell density does not affect global autophagy activity, suggesting the involvement of selective autophagy in SET degradation. SETBP1 directly binds to SET and protects it from cleavage by proteases. We found that high cell density increased SETBP1 mRNA and protein. Furthermore, altering the expression of SETBP1 suppressed the change in SET with cell density. Our data revealed a mechanism underlying the regulation of SET level, wherein increased cell density induces SETBP1 expression and protects SET from selective autophagy.