The acetylation of STAT3 at K685 attenuates NPM-ALK-induced tumorigenesis

Abstract

Nucleophosmin-anaplastic lymphoma kinase (NPM-ALK), a fusion protein generated by a chromosomal translocation, is a causative gene product of anaplastic large cell lymphoma (ALCL). It induces cell proliferation and tumorigenesis by activating the transcription factor, signal transducer and activator of transcription factor 3 (STAT3). We herein demonstrated that STAT3 underwent acetylation at K685 in a manner that was dependent on the kinase activity of NPM-ALK. To investigate the role of STAT3 acetylation in NPM-ALK-induced oncogenesis, we generated Ba/F3 cells expressing NPM-ALK in which STAT3 was silenced by shRNA, named STAT3-KD cells, and then reconstituted wild-type STAT3 or the STAT3 K685R mutant into these cells. The phosphorylation level of the K685R mutant at Y705 and S727 was significantly higher than that of wild-type STAT3 in STAT3-KD cells. The expression of STAT3 target genes, such as IL-6, Pim1, Pim2, and Socs3, was more strongly induced by the reconstitution of the K685R mutant than wild-type STAT3. In addition, the proliferative ability of STAT3-KD cells reconstituted with the K685R mutant was slightly higher than that of STAT3-KD cells reconstituted with wild-type STAT3. In comparisons with the inoculation of STAT3-KD cells reconstituted with wild-type STAT3, the inoculation of STAT3-KD cells reconstituted with the K685R mutant significantly enhanced tumorigenesis and hepatosplenomegaly in nude mice. Collectively, these results revealed for the first time that the acetylation of STAT3 at K685 attenuated NPM-ALK-induced oncogenesis.