RUNX2 recruits the NuRD(MTA1)/CRL4B complex to promote breast cancer progression and bone metastasis.

Runt-related transcription factor 2 (RUNX2) is an osteogenesis-related transcription factor that has emerged as a prominent transcription repressing factor in carcinogenesis. However, the role of RUNX2 in breast cancer metastasis remains poorly understood. Here, we show that RUNX2 recruits the metastasis-associated 1 (MTA1)/NuRD and the Cullin 4B (CUL4B)-Ring E3 ligase (CRL4B) complex to form a transcriptional-repressive complex, which catalyzes the histone deacetylation and ubiquitylation. Genome-wide analysis of the RUNX2/NuRD(MTA1)/CRL4B complex targets identified a cohort of genes including peroxisome proliferator-activated receptor alpha (PPARα) and superoxide dismutase 2 (SOD2), which are critically involved in cell growth, epithelial-to-mesenchymal transition (EMT) and invasion. We demonstrate that the RUNX2/NuRD(MTA1)/CRL4B complex promotes the proliferation, invasion, tumorigenesis, bone metastasis, cancer stemness of breast cancer in vitro and in vivo. Strikingly, RUNX2 expression is upregulated in multiple human carcinomas, including breast cancer. Our study suggests that RUNX2 is a promising potential target for the future treatment strategies of breast cancer.

Yin X ，Teng X ，Ma T ，Yang T ，Zhang J ，Huo M ，Liu W ，Yang Y ，Yuan B ，Yu H ，Huang W ，Wang Y ... -  《-》

CUL4B Promotes Breast Carcinogenesis by Coordinating with Transcriptional Repressor Complexes in Response to Hypoxia Signaling Pathway.

Cullin4B (CUL4B) is a scaffold protein of the CUL4B-Ring E3 ligase (CRL4B) complex. However, the role of CUL4B in the development of breast cancer remains poorly understood. Here it is shown that CRL4B interacts with multiple histone deacetylase (HDAC)-containing corepressor complexes, including MTA1/NuRD, SIN3A, CoREST, and NcoR/SMRT complexes. It is demonstrated that CRL4B/NuRD(MTA1) complexes cooccupy the E-cadherin and AXIN2 promoters, and could be recruited by transcription factors including Snail and ZEB2 to promote cell invasion and tumorigenesis both in vitro and in vivo. Remarkably, CUL4B responded to transformation and migration/invasion stimuli and is essential for multiple epithelial-mesenchymal transition (EMT) signaling pathways such as hypoxia. Furthermore, the transcription of CUL4B is directedly activated by hypoxia-inducible factor 1α (HIF1α) and repressed by the ERα-GATA3 axis. Overexpressing of CUL4B successfully induced CSC-like properties. Strikingly, CUL4B expression is markedly upregulated during breast cancer progression and correlated with poor prognosis. The results suggest that CUL4B lies at a critical crossroads between EMT and stem cell properties, supporting CUL4B as a potential novel target for the development of anti-breast cancer therapy.

Huang W ，Zhang J ，Huo M ，Gao J ，Yang T ，Yin X ，Wang P ，Leng S ，Feng D ，Chen Y ，Yang Y ，Wang Y ... -  《Advanced Science》

SMYD3 associates with the NuRD (MTA1/2) complex to regulate transcription and promote proliferation and invasiveness in hepatocellular carcinoma cells.

SMYD3, a member of the SET and MYND domain-containing (SMYD) family, is a histone methyltransferase (HMT) and transcription factor that plays an important role in transcriptional regulation in human carcinogenesis. Using affinity purification and mass spectrometry assays to identify SMYD3-associated proteins in hepatocellular carcinoma (HCC) cells, we found several previously undiscovered SMYD3-interacting proteins, including the NuRD (MTA1/2) complex, the METTL family, and the CRL4B complex. Transcriptomic analysis of the consequences of knocking down SMYD3, MTA1, or MTA2 in HCC cells showed that SMYD3/NuRD complex targets a cohort of genes, some of which are critically involved in cell growth and migration. qChIP analyses showed that SMYD3 knockdown led to a significant reduction in the binding of MTA1 or MTA2 to the promoters of IGFBP4 and led to a significant decrease in H4K20me3 and a marked increase in H4Ac at the IGFBP4 promoter. In addition, we demonstrated that SMYD3 promotes cell proliferation, invasion, and tumorigenesis in vivo and in vitro and found that its expression is markedly upregulated in human liver cancer. Knockdown of MTA1 or MTA2 had the same effect as knockdown of SMYD3 on proliferation and invasion of hepatocellular carcinoma cells. Catalytic mutant SMYD3 could not rescue the phenotypic effects caused by knockdown of SMYD3. Inhibitors of SMYD3 effectively inhibited the proliferation and invasiveness of HCC cells. These findings revealed that SMYD3 could transcriptionally repress a cohort of target genes expression by associating with the NuRD (MTA1/2) complex, thereby promoting the proliferation and invasiveness of HCC cells. Our results support the case for pursuing SMYD3 as a practical prognostic marker or therapeutic target against HCC.

Yang Y ，Qiu R ，Zhao S ，Shen L ，Tang B ，Weng Q ，Xu Z ，Zheng L ，Chen W ，Shu G ，Wang Y ，Zhao Z ，Chen M ，Ji J ... -  《-》

[CRL4B complex promotes the development of pancreatic cancer by inhibiting secreted frizzled related protein 1].

Chen Y ，Leng S ，Wang Y 《-》

The feedback loop between MTA1 and MTA3/TRIM21 modulates stemness of breast cancer in response to estrogen.

Zhang J ，Wang Y ，Zhang J ，Wang X ，Liu J ，Huo M ，Hu T ，Ma T ，Zhang D ，Li Y ，Guo C ，Yang Y ，Zhang M ，Yuan B ，Qin H ，Teng X ，Gao T ，Hao X ，Yu H ，Huang W ，Xu B ，Wang Y ... -  《Cell Death & Disease》