SMYD3 CONTRIBUTES TO SMALL CELL LUNG CANCER RESISTANCE TO ALKYLATION DAMAGE THROUGH RNF113A METHYLATION

Orateur : Nicolas REYNOIRD (IAB, Grenoble)

Although the lysine methyltransferase SMYD3 is overexpressed in many cancers and is generally associated with poor prognosis, its oncogenic functions still remain unclear. Here, we demonstrate the importance of SMYD3 in the development of small cell lung cancer (SCLC) and we identify the E3 ubiquitin ligase RNF113A as a novel substrate of SMYD3. RNF113A undergoes a SMYD3-dependent trimethylation at lysine K20 in cancer cells, which impairs its interaction with the phosphatase PP4, resulting to its increased phosphorylation. RNF113A is a phosphoprotein involved in alkylation damage response and this newly identified methylation-phosphorylation crosstalk appears as a key switch in controlling RNF113A E3-ligase activity and cellular chemoresistance to alkylating agents. Notably, the combination of alkylating chemotherapy and SMYD3 inhibition leads to a synergistic growth attenuation of SCLC patient derived xenografts. This work sheds light on a new mechanism of SMYD3 implication in cancer, through its participation in alkylation chemoresistance.

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