CUL4B regulates autophagy via JNK signaling in diffuse large B-cell lymphoma

Abstract

Aberrant expression of CUL4B was identified in various types of solid cancers. Cumulative evidences support the oncogenic role of CUL4B in cancers, including regulation of cell proliferation and signal transduction. However, its clinical value and potential pathogenic mechanism in diffuse large B-cell lymphoma (DLBCL) have not been described previously. Therefore, we hypothesize that overexpressed CUL4B may contribute to the pathogenesis of DLBCL. The aim of this study is to assess the expression and the biological function of CUL4B in DLBCL progression. In our study, CUL4B overexpression was observed in DLBCL tissues, and its upregulation was closely associated with poor prognosis in patients. Furthermore, the functional roles of CUL4B was detected both in vitro and in vivo. We demonstrated that silencing CUL4B could not only induce cell proliferation inhibition, cell cycle arrest, and motility attenuation of DLBCL cells in vitro, but also decrease tumor growth in DLBCL xenografts mice. In addition, we identified that CUL4B may act as a potent inductor of JNK phosphorylation in regulation of autophagy. Our findings demonstrated a significant role of CUL4B in the development and progression of DLBCL. CUL4B may act as a useful biomarker and a novel therapeutic target in DLBCL. ARTICLE HISTORY

Sirt6 promotes tumorigenesis and drug resistance of diffuse large B-cell lymphoma by mediating PI3K/Akt signaling

“…IHC and H&E staining were operated according to the manufacturers’ instructions as previously illustrated [ 8 , 23 ]. Detailed information was shown in Supplementary methods.…”

“…All mice were randomly cohorted into two groups. As previously illustrated [ 8 , 23 ], DLBCL cells (either transfected with shSirt6 vectors or empty control vectors) were subcutaneously injected to SCID-beige mice to establish xenograft models ( n = 8 per group). Details are described in Supplementary methods .…”

“…DLBCL is an extremely malignant disease characterized by dysregulation of cell proliferation and cells resistant to apoptosis [ 5 ]. Although 50–70% of DLBCL patients are responsive to standard rituximab based chemotherapy [ 6 – 8 ], the remaining relapsed or refractory patients usually die from disease progression [ 9 – 12 ]. Therefore, there is an urgent need to identify novel targeted treatment regimens for DLBCL patients.…”

Autophagy and Metabolism in Normal and Malignant Hematopoiesis

“…On the other hand, Li et al demonstrated that Cullin4B (CULB4) (a scaffold protein of the CUL4B-RING E3 ubiquitin ligase complex, highly expressed in DLBCL) is implicated in the positive regulation of autophagy, thus contributing to DLBCL progression. CUL4B deletion leads to inhibition of proliferation, an effect that could be attributed to the pro-survival ability mediated by autophagy [100]. Pharmacological inhibition of autophagy or knockdown of LC3B, ATG5, or p62/SQSTM1 in DLBCL OCI-Ly1 cells inhibited cell proliferation and induced apoptosis in vitro [101].…”

Therapeutic Modulation of Autophagy in Leukaemia and Lymphoma

“…On the contrary, Li Y. et al observed a link between Cullin4B (CUL4B) (a scaffold protein of the CUL4B-RING E3 ubiquitin ligase complex, highly expressed in DLBCL) and autophagy in the positive regulation of DLBCL progression. They showed that CUL4B regulating autophagy occurred through JNK signalling and that the inhibition of proliferation induced by CUL4B deletion may be attributed to the blocking of the pro-survival ability mediated by autophagy [109]. This last study highlights the complexity of autophagy regulation in DLBCL and the necessity to improve our knowledge on the role of autophagy in lymphoma development.…”