Abstract 4455: Fatty acid synthase-induced S6Kinase facilitates USP11-eIF4B complex formation for sustained oncogenic translation in DLBCL
Authors: Kapadia Bandish , Nanaji Nahid , Bhalla Kavita , Bhandary Binny , Lapidus Rena , Beheshti Afshin , Evens Andrew , Gartenhaus Ronald 
Published: August 2018

Fatty acid synthase (FASN) and protein translational machinery are two emergent therapeutic targets for cancer treatment, but their mutual dependency on each other for tumor propagation especially in diffuse B-cell large lymphoma (DLBCL) is still unknown. Therefore, we investigated the functional implication of enhanced FASN activity on protein translational machinery employing a panel of 7 DLCBL cell lines and 40 clinical samples. Inhibition of FASN activity by a specific inhibitor, C75 or shRNA mediated knockdown, suppressed de novo protein synthesis in SUDHL2, TMD8, Pfeiffer and HLY-1 (ABC-origin) cells, whereas SUDHL4, SUDHL6 and Toledo (GC-origin) cells showed minimal effect after C75 treatment or FASN knockdown. Assessing the core translational machinery, the eIF4B (eukaryotic initiation factor 4B) levels were depleted in a dose dependent manner of C75 treatment or shRNA mediated knock down of FASN in ABC-DLBCLs. Mechanistically, eIF4B undergoes ubiquitin mediated protein degradation upon FASN depletion. Depleting the expression of eIF4B significantly reduced the proliferative capacity of both FASN sensitive as well resistant DLBCL cells. Screening the interacting protein partners from available databases, we observed that USP11 interacts with and deubiquitinates eIF4B increasing its overall stability. Consistently, altering the expression of USP11 or its activity by either chemical inhibition or mutation significantly alters nascent peptide synthesis. Of functional significance, either down regulating USP11 or inhibition via small molecules significantly reduced the cell proliferation with increased apoptosis of both, FASN activity sensitive and resistant DLBCL cells. USP11 expression was also elevated in DLBCL tissues as evidenced by significantly higher staining. Significantly there is a strong correlation between USP11, FASN as well as eIF4B expression in DLBCL. Elucidating the basis for FASN not regulating GC DLBCL, we observed that sustained PI3K signalling in GC-DLBCL plays a key role in FASN dependent eIF4B stability. Detailed molecular analysis established that S6Kinase phosphorylates USP11 at Ser453, which regulates its interaction with, and stability of eIF4B thereby promoting proto-oncogene expression. These results together demonstrate that FASN activated S6Kinase induced eIF4B/USP11 axis is required for cell proliferation and survival by regulating the translation of proliferative and pro-survival mRNAs. Our findings support targeting the eIF4B/USP11 axis and provide a novel therapeutic option for patients with relapsed/refractory DLBCL.

Citation Format: Bandish Kapadia, Nahid Nanaji, Kavita Bhalla, Binny Bhandary, Rena Lapidus, Afshin Beheshti, Andrew Evens, Ronald Gartenhaus. Fatty acid synthase-induced S6Kinase facilitates USP11-eIF4B complex formation for sustained oncogenic translation in DLBCL [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4455.