Cullin3–KLHL25 ubiquitin ligase targets ACLY for degradation to inhibit lipid synthesis and tumor progression

Abstract

Increased lipid synthesis is a key characteristic of many cancers that is critical for cancer progression. ATP-citrate lyase (ACLY), a key enzyme for lipid synthesis, is frequently overexpressed or activated in cancer to promote lipid synthesis and tumor progression. Cullin3 (CUL3), a core protein for the CUL3-RING ubiquitin ligase complex, has been reported to be a tumor suppressor and frequently down-regulated in lung cancer. Here, we found that CUL3 interacts with ACLY through its adaptor protein, KLHL25 (Kelch-like family member 25), to ubiquitinate and degrade ACLY in cells. Through negative regulation of ACLY, CUL3 inhibits lipid synthesis, cell proliferation, and xenograft tumor growth of lung cancer cells. Furthermore, ACLY inhibitor SB-204990 greatly abolishes the promoting effect of CUL3 down-regulation on lipid synthesis, cell proliferation, and tumor growth. Importantly, low CUL3 expression is associated with high ACLY expression and poor prognosis in human lung cancer. In summary, our results identify CUL3-KLHL25 ubiquitin ligase as a novel negative regulator for ACLY and lipid synthesis and demonstrate that decreased CUL3 expression is an important mechanism for increased ACLY expression and lipid synthesis in lung cancer. These results also reveal that negative regulation of ACLY and lipid synthesis is a novel and critical mechanism for CUL3 in tumor suppression.

MiRNAs and mRNAs Analysis during Abdominal Preadipocyte Differentiation in Chickens

“…It has been argued that a single miRNA can simultaneously regulate the expression of multiple genes, and one gene can be regulated by multiple miRNAs [66]. miR-214 has been previously implicated in fibroblast differentiation of adipose-derived mesenchymal stem cells by targeting MFN2 [67], and regulates the differentiation of human hair follicle stem cells and bone marrow-derived mesenchymal stem cells [68,69]. ACLY, the putative target gene of miR-214, connects glucose metabolism to de novo synthesis of lipids [70].…”

Caloric Restriction Mimetics against Age-Associated Disease: Targets, Mechanisms, and Therapeutic Potential

“…Another ACLY inhibitor, the synthetic SB-204990, also stimulates autophagy in mice (Pietrocola et al, 2016) and mediates cholesterol and triglyceride reduction as well as tumor growth suppression in rodents (Pietrocola et al, 2016). Possibly, the Cullin3-KLHL25 (Kelch-like family member 25) ubiquitin ligase is responsible for the degradation of ACLY and subsequent inhibition of lipid synthesis and tumor progression (Zhang et al, 2016a). Future evaluation of the lifespan-and healthspan-promoting effects of SB-204990 must determine its potential as a CRM.…”

Dishevelled: A masterful conductor of complex Wnt signals

“…The KLHL12-Cullin-3 ubiquitin ligase complex negatively regulates Dishevelled [76]. Interestingly, Cullin-3 act as tumor suppressor and is downregulated in lung, liver, and breast cancer [172–175] which may correlate with the elevated levels of DVL proteins in those cancers.…”