Fbw7 Inhibits the Progression of Activated B-Cell Like Diffuse Large B-Cell Lymphoma by Targeting the Positive Feedback Loop of the LDHA/lactate/miR-223 Axis

Abstract

BackgroundF-box and WD repeat domain-containing 7 (Fbw7) is well known as a tumor suppressor and ubiquitin ligase which targets a variety of oncogenic proteins for proteolysis. We previously reported that Fbw7 promotes apoptosis in diffuse large B-cell lymphoma (DLBCL) through Fbw7-mediated ubiquitination of Stat3. This study aimed to identify the mechanism of Fbw7-mediated aerobic glycolysis reprogramming in DLBCL.MethodsExpression levels of Fbw7 and Lactate Dehydrogenase A (LDHA) in human DLBCL samples were evaluated by immunohistochemistry. Crosstalk between Fbw7 and LDHA signaling was analyzed by co-immunoprecipitation, ubiquitination assay, western blotting and mRNA quanlitative analyses. In vitro and in vivo experiments were used to assess the effect of the Fbw7-mediated LDHA/lactate/miR-223 axis on DLBCL cells growth.ResultsFbw7 could interact with LDHA to trigger its ubiquitination and degradation. Inversely, lactate negatively regulated Fbw7 via trigging the expression of miR-223, which targeted Fbw7 3’-UTR to inhibit its expression. In vivo and in vitro experiments revealed that miR-223 promoted tumor growth and that the effects of miR-223 on tumor growth were primarily related to the inhibition of Fbw7-mediated LDHA’s ubiquitination.ConclusionsWe demonstrated that the ubiquitin-ligase Fbw7 played a key role in LDHA-related aerobic glycolysis reprogramming in DLBCL. Our study uncovers a negative functional loop consisting of a Fbw7-mediated LDHA/lactate/miR-223 axis, which may support the future ABC-DLBCL therapy by targeting LDHA-related inhibition.

Modulation of the ubiquitin‐proteasome system by phytochemicals: Therapeutic implications in malignancies with an emphasis on brain tumors

“…86 It has been shown that the inactivation of FBW7-mediate degradation of lactate dehydrogenase A (LDHA) promoted large B-cell lymphoma tumor progression in vivo and in vitro. 87 Further, in adult T-cell leukemia-lymphoma, FBW7 repressed Notch signaling and hindered tumor growth. 88 However, contradictory reports exist concerning the role of FBW7 in cancers.…”

“…Likewise, FBW7 has been demonstrated to inhibit tumor growth in the lung, thyroid, melanoma, and cervical cancer 86 . It has been shown that the inactivation of FBW7‐mediate degradation of lactate dehydrogenase A (LDHA) promoted large B‐cell lymphoma tumor progression in vivo and in vitro 87 . Further, in adult T‐cell leukemia‐lymphoma, FBW7 repressed Notch signaling and hindered tumor growth 88 .…”

The metabolic role of lactate dehydrogenase in the growth of diffuse large B cell lymphoma

“…Inhibition of LDHA can limit the energy supply in cancer cells, thereby reducing metastasis and invasion of cancer cells 17 . Many studies have suggested that LDHA is a prognostic factor and a potential target for treatment in DLBCL [18][19][20][21][22] . Metabolism-related gene LDHA was highly expressed in malignant B cells in DLBCL tissue which was clustered using scRNA-seq 23 .…”

TRIM50 inhibits glycolysis and the malignant progression of gastric cancer by ubiquitinating PGK1

“…Aerobic glycolysis is the primary pathway by which tumor cells utilize glucose, known as the Warburg effect 12 , 13 . Numerous studies have indicated that tumor cells modulate the expression of glycolysis-related proteins through ubiquitin modification, thereby activating or inhibiting the glycolytic pathway 14 , 15 , 16 . For instance, the E3 ligase Fbw7 inhibits glycolysis in diffuse large B-cell lymphoma by promoting the ubiquitin-mediated degradation of LDHA 14 .…”

“…Numerous studies have indicated that tumor cells modulate the expression of glycolysis-related proteins through ubiquitin modification, thereby activating or inhibiting the glycolytic pathway 14 , 15 , 16 . For instance, the E3 ligase Fbw7 inhibits glycolysis in diffuse large B-cell lymphoma by promoting the ubiquitin-mediated degradation of LDHA 14 . HectH9, through K63-linked ubiquitination, facilitates the transfer of HK2 to mitochondria and enhances glycolysis in prostate cancer 15 .…”