F-box protein FBXO22 mediates polyubiquitination and degradation of KLF4 to promote hepatocellular carcinoma progression

Tian, Xin; Dai, Shun‐Dong; Sun, Jing; Jin, Guojiang; Jiang, Shenyi; Meng, Fandong; Li, Yan; Wu, Di; Jiang, Youyu

doi:10.18632/oncotarget.4082

Cited by 45 publications

(36 citation statements)

References 34 publications

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“…Thus, we conclude that FBXO32 is a liable E3 ligase that mediates KLF4 turnover in breast cancer cells. Interestingly, a recent study reported that FBXO22 degrades KLF4 in hepatocellular carcinoma, 42 whereas in our situation knockdown of FBXO22 had negligible effect on KLF4 protein level.…”

Section: Discussioncontrasting

confidence: 83%

FBXO32 suppresses breast cancer tumorigenesis through targeting KLF4 to proteasomal degradation

et al. 2017

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Krüppel-like factor 4 (KLF4, GKLF) is a zinc-finger transcription factor involved in a large variety of cellular processes, including apoptosis, cell cycle progression, as well as stem cell renewal. KLF4 is critical for cell fate decision and has an ambivalent role in tumorigenesis. Emerging data keep reminding us that KLF4 dysregulation either facilitates or impedes tumor progression, making it important to clarify the regulating network of KLF4. Like most transcription factors, KLF4 has a rather short half-life within the cell and its turnover must be carefully orchestrated by ubiquitination and ubiquitin–proteasome system. To better understand the mechanism of KLF4 ubiquitination, we performed a genome-wide screen of E3 ligase small interfering RNA library based on western blot and identified SCF-FBXO32 to be a new E3 ligase, which is responsible for KLF4 ubiquitination and degradation. The F-box domain is critical for FBXO32-dependent KLF4 ubiquitination and degradation. Furthermore, we demonstrated that FBXO32 physically interacts with the N-terminus (1–60 aa) of KLF4 via its C-terminus (228–355 aa) and directly targets KLF4 for ubiquitination and degradation. We also found out that p38 mitogen-activated protein kinase pathway may be implicated in FBXO32-mediated ubiquitination of KLF4, as p38 kinase inhibitor coincidently abrogates endogenous KLF4 ubiquitination and degradation, as well as FBXO32-dependent exogenous KLF4 ubiquitination and degradation. Finally, FBXO32 inhibits colony formation in vitro and primary tumor initiation and growth in vivo through targeting KLF4 into degradation. Our findings thus further elucidate the tumor-suppressive function of FBXO32 in breast cancer. These results expand our understanding of the posttranslational modification of KLF4 and of its role in breast cancer development and provide a potential target for diagnosis and therapeutic treatment of breast cancer.

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Section: Discussioncontrasting

confidence: 83%

FBXO32 suppresses breast cancer tumorigenesis through targeting KLF4 to proteasomal degradation

et al. 2017

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“…It should be noted that Johmura et al (31) have observed proliferative defects in immortalized retina pigmented epithelial cells depleted of FBXO22 and in FBXO22 −/− mouse epithelial fibroblasts. Similar growth defects were reported in human liver cancer HepG2 cells treated with shRNA against FBXO22 (39). In addition, overexpression of FBXO22 accelerated cell proliferation and colony formation in a number of breast cancer cells (40).…”

Section: Low Fbxo22 Expression Is Correlated With Worse Survival In Hsupporting

confidence: 76%

SCF ^FBXO22 targets HDM2 for degradation and modulates breast cancer cell invasion and metastasis

Bai

Cao

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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Human homolog of mouse double minute 2 (HDM2) is an oncogene frequently overexpressed in cancers with poor prognosis, but mechanisms of controlling its abundance remain elusive. In an unbiased biochemical search, we discovered Skp1-Cullin 1-FBXO22-ROC1 (SCF FBXO22 ) as the most dominating HDM2 E3 ubiquitin ligase from human proteome. The results of protein decay rate analysis, ubiquitination, siRNA-mediated silencing, and coimmunoprecipitation experiments support a hypothesis that FBXO22 targets cellular HDM2 for ubiquitin-dependent degradation. In human breast cancer cells, FBXO22 knockdown (KD) increased cell invasiveness, which was driven by elevated levels of HDM2. Moreover, mouse 4T1 breast tumor model studies revealed that FBXO22 KD led to a significant increase of breast tumor cell metastasis to the lung. Finally, low FBXO22 expression is correlated with worse survival and high HDM2 expression in human breast cancer. Altogether, these findings suggest that SCF FBXO22 targets HDM2 for degradation and possesses inhibitory effects against breast cancer tumor cell invasion and metastasis.HDM2 abundance | E3 SCF-FBXO22 | breast cancer metastasis M ouse double minute 2 (MDM2; human homolog, HDM2) is defined as a RING-type E3 ubiquitin ligase with a prominent role in tumorigenesis, acting both as an oncogene and a tumor suppressor (1). MDM2/HDM2 is best understood for its oncogenic role, which is executed predominantly via a mechanism that utilizes the intrinsic E3 ligase activity to target the p53 tumor suppressor for ubiquitin-dependent degradation (2, 3). However, accumulating evidence suggests p53-independent mechanisms that contribute to MDM2/HDM2's oncogene function as well (4).As noted by a large body of clinical studies, HDM2 amplification and overexpression are common to a variety of cancers that often have a poor prognosis (4-6). Elevated levels of HDM2 are regarded as a significant risk factor in distant metastasis (7). Although, mechanistically, such phenomena can be attributed to the ability of HDM2 to drive p53 degradation (5), emerging studies have revealed additional contributing mechanisms involving previously underappreciated activity by MDM2/ HDM2 to promote tumor cell invasiveness (8). In this regard, MDM2 was shown to act as an E3 ligase to target epithelial marker E-cadherin for ubiquitin-dependent degradation (8). However, a subsequent study suggests that, in renal cell carcinoma, MDM2 can promote cell motility and invasiveness without the function of MDM2 RING finger domain (9). Another mechanism may involve matrix metalloproteinase (MMP) capable of degrading membrane-associated extracellular proteins, a process critically implicated for metastasis (10). Intriguingly, MDM2 overexpression was found to transcriptionally up-regulate the expression of MMP-9 (11), although the precise mechanism remains to be elucidated.The compelling association between HDM2 overexpression and aggressive cancer malignancy argues for a potentially critical importance concerning cellular mechanisms for the contro...

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“…In hepatocellular carcinoma (HCC) cells, SCF(Fbxo22) can ubiquitinate KLF4 causing its degradation, promoting cell proliferation, anchorage independence, and invasiveness. These phenotypes and the increased Fbxo22 levels found in patient samples suggest a TSG role for KLF4 in this cell type (71).…”

Section: Sustaining Proliferation By Blocking Differentiationmentioning

confidence: 84%

F-box protein interactions with the hallmark pathways in cancer

Randle

Laman

2016

Seminars in Cancer Biology

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F-box proteins (FBP) are the substrate specifying subunit of Skp1-Cul1-FBP (SCF)-type E3 ubiquitin ligases and are responsible for directing the ubiquitination of numerous proteins essential for cellular function. Due to their ability to regulate the expression and activity of oncogenes and tumour suppressor genes, FBPs themselves play important roles in cancer development and progression. In this review, we provide a comprehensive overview of FBPs and their targets in relation to their interaction with the hallmarks of cancer cell biology, including the regulation of proliferation, epigenetics, migration and invasion, metabolism, angiogenesis, cell death and DNA damage responses. Each cancer hallmark is revealed to have multiple FBPs which converge on common signalling hubs or response pathways. We also highlight the complex regulatory interplay between SCF-type ligases and other ubiquitin ligases. We suggest six highly interconnected FBPs affecting multiple cancer hallmarks, which may prove sensible candidates for therapeutic intervention.

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F-box protein FBXO22 mediates polyubiquitination and degradation of KLF4 to promote hepatocellular carcinoma progression

Cited by 45 publications

References 34 publications

FBXO32 suppresses breast cancer tumorigenesis through targeting KLF4 to proteasomal degradation

FBXO32 suppresses breast cancer tumorigenesis through targeting KLF4 to proteasomal degradation

SCF ^FBXO22 targets HDM2 for degradation and modulates breast cancer cell invasion and metastasis

F-box protein interactions with the hallmark pathways in cancer

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F-box protein FBXO22 mediates polyubiquitination and degradation of KLF4 to promote hepatocellular carcinoma progression

Cited by 45 publications

References 34 publications

FBXO32 suppresses breast cancer tumorigenesis through targeting KLF4 to proteasomal degradation

FBXO32 suppresses breast cancer tumorigenesis through targeting KLF4 to proteasomal degradation

SCF FBXO22 targets HDM2 for degradation and modulates breast cancer cell invasion and metastasis

F-box protein interactions with the hallmark pathways in cancer

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SCF ^FBXO22 targets HDM2 for degradation and modulates breast cancer cell invasion and metastasis