Fbxo22-mediated KDM4B degradation determines selective estrogen receptor modulator activity in breast cancer

Johmura, Yoshikazu; Maeda, Ichiro; Narumi, Shosaku; Wu, Wenwen; Goda, Atsushi; Morita, Mariko; Yamaguchi, Kiyoshi; Yamamoto, Mizuki; Nagasawa, Satoi; Kojima, Yasuyuki; Tsugawa, Koichiro; Inoue, Nobuyuki; Miyoshi, Yasuo; Osako, Tomo; Akiyama, Futoshi; Maruyama, Reo; Inoue, Jun–ichiro; Furukawa, Yoichi; Ohta, Tomohiko; Nakanishi, Makoto

doi:10.1172/jci121679

Cited by 47 publications

(46 citation statements)

References 51 publications

(58 reference statements)

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“…In addition, the correlation of low FBXO22 expression with poor prognosis in human breast cancer patients revealed in the present work ( Fig. 6 A and B and SI Appendix, Tables S1 and S3) was supported by recent studies from Sun et al (40) and Johmura et al (41).…”

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

confidence: 91%

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

confidence: 91%

“…5). Finally, the effects by FBXO22 on breast cancer could be mediated by targeted degradation of KDM4A (26), which was shown to modulate estrogen receptor modulator activity (41).…”

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

confidence: 99%

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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“…In mammals, there are~70 F-box proteins, which generate three families, the F-box and WD40 domain (FBXW) family, the F-box and Leu-rich repeat (FBXL) family and F-box only (FBXO) proteins such as FBXO22. To date, some substrates of FBXO22 have been reported, including BTB and CNC homolog 1 (BACH1) 34 , Krueppel-like factor 4 35 , P53 36 , serine/threonine-protein kinase (STK11 or LKB1) 37 and lysine-specific demethylase 4B (KDM4B) 38 . The tumor promoting role of FBXO22 has been presented by some reports in liver cancer 35 , lung cancer 37 , and breast cancer 39 , while an inhibitory role towards cancer metastasis has also been proposed in lung cancer 34 and breast cancer 39 .…”

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confidence: 99%

FBXO22 degrades nuclear PTEN to promote tumorigenesis

Zhang

et al. 2020

Nat Commun

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Nuclear localization of PTEN is essential for its tumor suppressive role, and loss of nuclear PTEN is more prominent than cytoplasmic PTEN in many kinds of cancers. However, nuclear PTEN-specific regulatory mechanisms were rarely reported. Based on the finding that nuclear PTEN is more unstable than cytoplasmic PTEN, here we identify that F-box only protein 22 (FBXO22) induces ubiquitylation of nuclear but not cytoplasmic PTEN at lysine 221, which is responsible for the degradation of nuclear PTEN. FBXO22 plays a tumor-promoting role by ubiquitylating and degrading nuclear PTEN. In accordance, FBXO22 is overexpressed in various cancer types, and contributes to nuclear PTEN downregulation in colorectal cancer tissues. Cumulatively, our study reports the mechanism to specifically regulate the stability of nuclear PTEN, which would provide the opportunity for developing therapeutic strategies aiming to achieve complete reactivation of PTEN as a tumor suppressor.

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“…In contrast to SKP2, much less is known about FBXO22, which has both a positive and negative role in breast cancer progression and metastasis, respectively ( 45 ). Furthermore, Fbxo22 -depletion resulted in the reduced response of ER-positive breast cancer cells to tamoxifen, and the overexpression of JAB1 has been shown to confer tamoxifen resistance in ER-positive breast cancer ( 46 , 47 ). In our study, CSN5i-3 treatment completely abolished FBXO22 expression ( Figure 7E ).…”

Section: Discussionmentioning

confidence: 99%

The crucial p53-dependent oncogenic role of JAB1 in osteosarcoma in vivo

et al. 2020

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Osteosarcoma (OS) is the most common primary bone cancer and ranks amongst the leading causes of cancer mortality in young adults. J un a ctivation domain b inding protein 1 ( JAB1 ) is overexpressed in many cancers and has recently emerged as a novel target for cancer treatment. However, the role of JAB1 in osteosarcoma was virtually unknown. In this study, we demonstrate that JAB1 -knockdown in malignant osteosarcoma cell lines significantly reduced their oncogenic properties, including proliferation, colony formation, and motility. We also performed RNA-sequencing analysis in JAB1 -knockdown OS cells and identified 4110 genes that are significantly differentially expressed. This demonstrated for the first time that JAB1 regulates a large and specific transcriptome in cancer. We also found that JAB1 is overexpressed in human OS and correlates with a poor prognosis. Moreover, we generated a novel mouse model that overexpresses Jab1 specifically in osteoblasts upon a TP53 heterozygous sensitizing background. Interestingly, by 13 months of age, a significant proportion of these mice spontaneously developed conventional OS. Finally, we demonstrate that a novel, highly specific small molecule inhibitor of JAB1, CSN5i-3, reduces osteosarcoma cell viability and has specific effects on the ubiquitin-proteasome system in OS. Thus, we show for the first time that the overexpression of JAB1 in vivo can result in accelerated spontaneous tumor formation in a p53-dependent manner. In summary, JAB1 might be a unique target for the treatment of osteosarcoma and other cancers.

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Fbxo22-mediated KDM4B degradation determines selective estrogen receptor modulator activity in breast cancer

Cited by 47 publications

References 51 publications

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

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

FBXO22 degrades nuclear PTEN to promote tumorigenesis

The crucial p53-dependent oncogenic role of JAB1 in osteosarcoma in vivo

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Fbxo22-mediated KDM4B degradation determines selective estrogen receptor modulator activity in breast cancer

Cited by 47 publications

References 51 publications

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

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

FBXO22 degrades nuclear PTEN to promote tumorigenesis

The crucial p53-dependent oncogenic role of JAB1 in osteosarcoma in vivo

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

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