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

Abstract

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...

Regulator of cullins-1 (ROC1) negatively regulates the Gli2 regulator SUFU to activate the hedgehog pathway in bladder cancer

“…In our current study, we revealed that exogenous overexpression of ROC1 promoted bladder cancer cell proliferation, whereas knockdown of ROC1 expression inhibited tumor growth through induction of the G2/M arrest. Consistent with our current nding and further supporting the importance of CRL in the regulation of tumor cell proliferation, the suppression of the CRL activity using the FBXO22 silencing inhibited cancer progression through targeting of HDM2 for degradation in breast cancer [12]. Mechanistically, DNA damage is the most common cause to induce cell G2/M arrest [18].…”

“…ROC1 contains a small zinc-binding domain (the RING nger), which is evolutionarily conserved and is essential in embryonic development, while aberrant ROC1 expression led to CRL dysfunction and embryonic lethality [7,8]. ROC1 is also essential in maintenance of the genome integrity and cancer development [8][9][10][11][12]. Our previous studies demonstrated that ROC1 protein was overexpressed in bladder cancer tissues, while knockdown of ROC1 expression reduced the CRL activity, triggered accumulation of its speci c substrates (such as p21, p27, and DEPTOR), leading to suppression of tumor progression [13,14].…”

FBXO22, an epigenetic multiplayer coordinating senescence, hormone signaling, and metastasis

“…Intriguingly, FBXO22 was reported to ubiquitylate SNAIL for degradation. This degradation was dependent on the phosphorylation of SNAIL by GSK3β 8,59 . In agreement with GSK3β as a negative regulator of EMT, activation of Wnt signaling by suppression of GSK3β, is known to induce EMT 60 …”

Screening and Authentication of Key Genes and Prognostic Value Analysis in Oligodendroglial Tumors

“…Zhu XN et al [29] nding show that FBXO22 is highly expressed in human lung cancer at the protein level. Bai J et al [30] reveal that SCF-FBXO22 targets HDM2 for degradation and possesses inhibitory effects against breast cancer tumor cell invasion and metastasis. We also found the increased FBXO22 expression in oligodendroglial tumor samples and proved its prognostic value for cancer patients.…”