Central spindle proteins and mitotic kinesins are direct transcriptional targets of MuvB, B-MYB and FOXM1 in breast cancer cell lines and are potential targets for therapy

Wolter, Patrick; Hanselmann, Steffen; Pattschull, Grit; Schruf, Eva; Gaubatz, Stefan

doi:10.18632/oncotarget.14466

Cited by 36 publications

(23 citation statements)

References 47 publications

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“…S5). Decreased levels of either the MuvB complex protein LIN9 or B-Myb were effective in reducing cancer proliferation and tumor mass (38,39). Targeting this interface would disrupt the activator MMB complex and potentially restore the DREAM complex to promote quiescence and tumor dormancy (16,28).…”

Section: Discussionmentioning

confidence: 99%

Structural mechanism of Myb–MuvB assembly

Guiley

Iness

Saini

et al. 2018

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

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The MuvB transcriptional regulatory complex, which controls cell-cycle-dependent gene expression, cooperates with B-Myb to activate genes required for the G2 and M phases of the cell cycle. We have identified the domain in B-Myb that is essential for the assembly of the Myb-MuvB (MMB) complex. We determined a crystal structure that reveals how this B-Myb domain binds MuvB through the adaptor protein LIN52 and the scaffold protein LIN9. The structure and biochemical analysis provide an understanding of how oncogenic B-Myb is recruited to regulate genes required for cell-cycle progression, and the MMB interface presents a potential therapeutic target to inhibit cancer cell proliferation.

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Section: Discussionmentioning

confidence: 99%

Structural mechanism of Myb–MuvB assembly

Guiley

Iness

Saini

et al. 2018

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

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“…Phosphorylated FOXM1 and the MuvB complex remain bound to the DNA and regulate expression of genes important for the G2/M transition and successful completion of mitosis, including AURKA , AURKB , PLK1 , and KIF20A (39, 49, 52), all of which are also suppressed with BETi treatment. In addition, six mitotic kinesins (KIF4A, KIF23, KIF2C, KIF14, KIFC1, and KIF20A) and two microtubule-associated non-motor proteins (PRC1 and CEP55) that have known functions in mitosis and cytokinesis are direct targets of MuvB, B-MYB, and FOXM1 in breast cancer (54). Expression of genes encoding these proteins as well as eight additional mitotic kinesins (36) were downregulated following BETi treatment.…”

Section: Discussionmentioning

confidence: 99%

Mitotic Vulnerability in Triple-Negative Breast Cancer Associated with LIN9 Is Targetable with BET Inhibitors

et al. 2017

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Triple-negative breast cancers (TNBC) are highly aggressive, lack FDA-approved targeted therapies, and frequently recur, making the discovery of novel therapeutic targets for this disease imperative. Our previous analysis of the molecular mechanisms of action of Bromodomain and extraterminal protein inhibitors (BETi) in TNBC revealed these drugs cause multinucleation, indicating BET proteins are essential for efficient mitosis and cytokinesis. Here, using live cell imaging, we show that BET inhibition prolonged mitotic progression and induced mitotic cell death, both of which are indicative of mitotic catastrophe. Mechanistically, the mitosis regulator LIN9 was a direct target of BET proteins that mediated the effects of BET proteins on mitosis in TNBC. While BETi have been proposed to function by dismantling super-enhancers (SE), the LIN9 gene lacks a SE but was amplified or overexpressed in the majority of TNBCs. In addition, its mRNA expression predicted poor outcome across breast cancer subtypes. Together, these results provide a mechanism for cancer selectivity of BETi that extends beyond modulation of SE-associated genes and suggest that cancers dependent upon LIN9 overexpression may be particularly vulnerable to BETi.

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“…8 Finally, several of the MMB downstream targets upregulated in late S-G2 phases of the cell cycle, such as Aurora kinase A, Polo-like kinase B and others have been proposed for developing anti-cancer therapies. 8,59 Better understanding of the mechanisms that bring about high expression of these genes in cancer will be important to inform the future pre-clinical and clinical studies and to optimize patient stratification. Overall, we have shown a novel model describing some of the molecular processes underlying deregulated cell cycle gene expression in cancers with B-Myb amplification or overexpression.…”

Section: Discussionmentioning

confidence: 99%

The cell cycle gene regulatory DREAM complex is disrupted by high expression of oncogenic B-Myb

Iness

Felthousen

Ananthapadmanabhan

et al. 2017

Preprint

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The oncogene MYBL2 (encoding B-Myb) is a poor prognostic biomarker in many cancers. B-Myb interacts with the MuvB core of five proteins (LIN9, LIN37, LIN52, LIN53/RBBP4, and LIN54) to form the MMB (Myb-MuvB) complex and promotes expression of late cell cycle genes necessary for progression through mitosis. Both MYBL2 amplification and over-expression are associated with deregulation of the cell cycle and increased cell proliferation. Alternatively, by interacting with E2F4-DP1 and p130 or p107, the MuvB core becomes part of the DREAM complex (DP, RB-like, E2F, and MuvB). The DREAM complex opposes MMB by globally repressing cell cycle genes in G0/G1, maintaining the cell in a quiescent state. However, the specific mechanism by which B-Myb alters the cell cycle is not well understood. Our analysis of The Cancer Genome Atlas data revealed significant upregulation of DREAM and MMB target genes in breast and ovarian cancer with MYBL2 gain. Given that most of the DREAM target genes are not directly regulated by B-Myb, we investigated the effects of B-Myb on DREAM formation. We found that depletion of B-Myb results in increased DREAM formation in human cancer cells, while its overexpression inhibits DREAM formation in the non-transformed cells. Since the MuvB core subunit LIN52 is essential for assembly of both the DREAM and MMB complexes, we tested whether B-Myb disrupts DREAM by sequestering LIN52. Overexpression of LIN52 did not increase either DREAM or MMB formation, but instead increased the turnover rate of the endogenous LIN52 protein. Interestingly, co-expression of B-Myb increased the expression of both endogenous and overexpressed LIN52 while knockdown of B-Myb had an opposite effect. We found that regulation of LIN52 occurs at the protein level, and that activity of DYRK1A kinase, the enzyme that triggers DREAM complex formation by phosphorylating LIN52, is required for this regulation. These findings are the first to implicate B-Myb in the disassembly of the DREAM complex and offer insight into the underlying mechanisms of poor prognostic value of MYBL2 amplification in cancer. We conclude that B-Myb mediates its oncogenic effects not only by increasing mitotic gene expression by the MMB complex, but also by broad disruption of cell cycle gene regulatory programs through compromised DREAM formation.

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Central spindle proteins and mitotic kinesins are direct transcriptional targets of MuvB, B-MYB and FOXM1 in breast cancer cell lines and are potential targets for therapy

Cited by 36 publications

References 47 publications

Structural mechanism of Myb–MuvB assembly

Structural mechanism of Myb–MuvB assembly

Mitotic Vulnerability in Triple-Negative Breast Cancer Associated with LIN9 Is Targetable with BET Inhibitors

The cell cycle gene regulatory DREAM complex is disrupted by high expression of oncogenic B-Myb

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