Chromosomal translocation-derived aberrant Rab22a drives metastasis of osteosarcoma

Liao, Dan; Zhong, Li; Yin, Junqiang; Zeng, Cuiling; Wang, Xin; Huang, Xiuzhen; Chen, Jinna; Zhang, Hong; Zhang, Ruhua; Guan, Xin‐Yuan; Shuai, Xintao; Sui, Jianhua; Gao, Song; Deng, Wuguo; Zeng, Yi‐Xin; Shen, Jingnan; Chen, Jian; Kang, Tiebang

doi:10.1038/s41556-020-0522-z

Cited by 38 publications

(55 citation statements)

References 49 publications

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“…Antibodies used in this study were as follows: Flag (D6W5B) Rabbit mAb (CST, 8146S), HA-Tag (C29F4) Rabbit mAb (CST, 3724), anti-Acetylated-Lysine Antibody (CST, 9441s), Acetylated lysine polyclonal antibody (PAB10348, abnova), RhoA (67B9) Rabbit mAb (CST, #2117S), β-Tubulin (9F3) Rabbit mAb (CST,#2128), GAPDH (D16H11) Rabbit mAb (CST, #5174), SirT1 (D1D7) Rabbit mAb (CST, #9475) ,HDAC6(D2E5) Rabbit mAb (CST, #7558), BD Pharmingen™ Purified Mouse Anti-Human p300 (BD, 554215), CBP (D6C5) Rabbit mAb (CST, #7389). mAb RAD5-8 and hRAD5-8-v1-R5 antibody were generated as previously described 8 .…”

Section: Methodsmentioning

confidence: 99%

“…Redundancy in growth signals and high heterogeneity lead to no effective molecular therapeutic target in osteosarcoma 7 . Our group has just identified a fusion gene termed Rab22a-NeoF1, which is a driver for osteosarcoma lung metastasis and may be potential target for patients with osteosarcoma metastases 8 .…”

Section: Introductionmentioning

confidence: 99%

“…Rab22a-NeoF1 fusion protein has 186aa comprising the 1-38aa of Rab22a (Rab22a 1-38 ) and the 39-186aa encoded from the inverted intron of DOK5 . The Rab22a 1-38 plays a decisive role in driving osteosarcoma lung metastasis by activating RhoA through binding to SmgGDS607 via Arg4 (R4) and Lys7 (K7) 8 . RhoA is a member of the Rho GTPase family that plays key roles in metastasis, and SmgGDS607 is an isoform of SmgGDS (PAR1GDS1), which is a specific GEF protein for RhoA/RhoC.…”

Section: Introductionmentioning

confidence: 99%

“…According to the full-length Rab22a protein model 9 , K7 is blocked by the main chain oxygen atoms of Met73, Tyr74 and Arg76, whereas R4 is surface-exposed. In Rab22a-NeoF1, however, they may both be exposed because of the truncation and possibly different folding from that of wild-type Rab22a, insulting in a much higher binding affinity of Rab22a-NeoF1 to SmgGDS607 compared to wild type Rab22a 8 . Lysine residue in proteins is often modified by many post-translational modifications, such as methylation, ubiquitination and acetylation, which play an important role in protein-protein interactions, protein subcellular localization, protein stability and so on 10 - 18 .…”

Section: Introductionmentioning

confidence: 99%

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Acetylation dependent functions of Rab22a-NeoF1 Fusion Protein in Osteosarcoma

Liang

Wang

et al. 2020

Theranostics

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Background: Rab22a-NeoF1 fusion gene containing the 1-38aa of Rab22a (Rab22a 1-38 ) plays a decisive role in driving tumor metastasis by activating RhoA via binding to SmgGDS607. However, its intercellular regulation remains unknown. Methods: The Lys7 (K7) acetylation of Rab22a-NeoF1 was initially identified by mass spectrum. Co-transfection, immunoprecipitation and Western blotting were used to characterize the acetyltransferases and deacetylases responsible for the K7 acetylation of Rab22a-NeoF1, and to define the interaction of proteins. The specificity of K7 acetylation of Rab22a-NeoF1 was determined by its specific anti-K7ac-Rab22a-NeoF1 antibody and its K7R mutant. RhoA-GTP was measured by RhoA activation assay. The migration and invasion were assessed by Transwell assay without and with Matrigel matrix, respectively. The orthotopic osteosarcoma metastasis model in vivo was used to monitor the lung metastases of U2OS/MTX300-Luc stably expressing Vector, Rab22a-NeoF1 or its K7R mutant with or without C646, a relatively specific inhibitor of p300/CBP. The unpaired Student t test was used for the statistical significance. Results: The K7 of Rab22a-NeoF1 is acetylated by p300/CBP while is de-acetylated by both HDAC6 and SIRT1. The K7R mutant of Rab22a-NeoF1 lacks its binding to SmgGDS607 and subsequently lost its promoting functions, such as activation of RhoA, cell migration, invasion and lung metastasis in osteosarcoma in vitro and in viv o, which are also diminished by p300/CBP inhibitor C646. Conclusion: The promoting function of Rab22a-NeoF1 is dependent on its K7 acetylation in osteosarcoma, and targeting this acetylation (e.g., C646) may benefit cancer patients, in particular osteosarcoma patients, who are positive for the Rab22a 1-38 .

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Acetylation dependent functions of Rab22a-NeoF1 Fusion Protein in Osteosarcoma

Liang

Wang

et al. 2020

Theranostics

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“…3 For example, the high instability of somatic genome in osteosarcoma, including chromothripsis, chromosomal aneuploidy, and chromosomal rearrangements, could contribute to the production of truncated or fusion proteins, and inhibit many key tumor suppressor genes like TP53 and ATRX, triggering tumor cells migration. 1 Although many fusion proteins have been validated as effective targets for treating several cancer types in the clinic, there are no such therapies for osteosarcoma. To comprehensively explore this novel area, Kang et al used TopHat-fusion and SQUID algorithms to screen out some related structural variations in metastatic osteosarcoma.…”

mentioning

confidence: 99%

Rab22a-NeoF1: a promising target for osteosarcoma patients with lung metastasis

Xie

Zhang

Tao

2020

Sig Transduct Target Ther

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Targeting the Lysosomal Degradation of Rab22a‐NeoF1 Fusion Protein for Osteosarcoma Lung Metastasis

et al. 2022

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Rab22a-NeoF fusion protein has recently been reported as a promising target for osteosarcoma lung metastasis. However, how this fusion protein is regulated in cells remains unknown. Here, using multiple screenings, it is reported that Rab22a-NeoF1 fusion protein is degraded by an E3 ligase STUB1 via the autophagy receptor NDP52-mediated lysosome pathway, which is facilitated by PINK1 kinase. Mechanistically, STUB1 catalyzes the K63-linked ubiquitin chains on lysine112 of Rab22a-NeoF1, which is responsible for the binding of Rab22a-NeoF1 to NDP52, resulting in lysosomal degradation of Rab22a-NeoF1. PINK1 is able to phosphorylate Rab22a-NeoF1 at serine120, which promotes ubiquitination and degradation of Rab22a-NeoF1. Consistently, by upregulating PINK1, Sorafenib and Regorafenib can inhibit osteosarcoma lung metastasis induced by Rab22a-NeoF1. These findings reveal that the lysosomal degradation of Rab22a-NeoF1 fusion protein is targetable for osteosarcoma lung metastasis, proposing that Sorafenib and Regorafenib may benefit cancer patients who are positive for the RAB22A-NeoF1 fusion gene.

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Chromosomal translocation-derived aberrant Rab22a drives metastasis of osteosarcoma

Cited by 38 publications

References 49 publications

Acetylation dependent functions of Rab22a-NeoF1 Fusion Protein in Osteosarcoma

Acetylation dependent functions of Rab22a-NeoF1 Fusion Protein in Osteosarcoma

Rab22a-NeoF1: a promising target for osteosarcoma patients with lung metastasis

Targeting the Lysosomal Degradation of Rab22a‐NeoF1 Fusion Protein for Osteosarcoma Lung Metastasis

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