Acetylation of histone H3 prevents resistance development caused by chronic mTOR inhibition in renal cell carcinoma cells.

Chronic mTOR inhibition may induce resistance development in renal cell carcinoma (RCC). We analyzed whether long-term exposure of RCC cells to the mTOR-inhibitor RAD001 evokes resistance and whether additional targeting histone deacetylases (HDAC) by valproic acid (VPA) overcomes RAD001 resistance. It is demonstrated that responsiveness to either drug alone is lost over time, evidenced by increased cell growth, proliferation and de-differentiation. However, drug sensitivity was conserved when RAD001 and VPA were applied in concert. Molecular analysis particularly revealed strong re-activation of Akt under chronic RAD001 or diminished histone H3 acetylation under chronic VPA single drug exposure. Combined drug application did not inactivate Akt but rather resulted in H3 acetylation remaining high while RCC cell growth was still reduced. siRNA experiments revealed that histone H3 acetylation is responsible for preserving drug sensitivity in RCCs.