TEAD1 and c-Cbl are novel prostate basal cell markers that correlate with poor clinical outcome in prostate cancer

Knight, Jennifer; Shepherd, Christopher J.; Rizzo, Siân; Brewer, Daniel; Jhavar, Sameer; Dodson, Andrew; Cooper, Christopher S.; Eeles, Rosalind; Falconer, Alison; Kovács, Gyula; Garrett, Michelle D.; Norman, A.; Shipley, Janet; Hudson, David L.

doi:10.1038/sj.bjc.6604774

Cited by 77 publications

(80 citation statements)

References 56 publications

(52 reference statements)

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“…We have also revealed that E6-mediated upregulation of A3B is primarily caused by increased levels of TEAD1/4. A3B and TEAD1/4 are reported to be upregulated in various types of human cancer, and each has been proposed to play important roles in carcinogenesis (5)(6)(7)(8)(9)(28)(29)(30)(31)(32). This study thus establishes a novel transcriptional link between these oncogenic factors.…”

Section: Discussionmentioning

confidence: 72%

Human Papillomavirus 16 E6 Upregulates APOBEC3B via the TEAD Transcription Factor

Mori

Takeuchi

Ishii

et al. 2017

J Virol

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The cytidine deaminase APOBEC3B (A3B) underlies the genetic heterogeneity of several human cancers, including cervical cancer, which is caused by human papillomavirus (HPV) infection. We previously identified a region within the A3B promoter that is activated by the viral protein HPV16 E6 in human keratinocytes. Here, we discovered three sites recognized by the TEAD family of transcription factors within this region of the A3B promoter. Reporter assays in HEK293 cells showed that exogenously expressed TEAD4 induced A3B promoter activation through binding to these sites. Normal immortalized human keratinocytes expressing E6 (NIKS-E6) displayed increased levels of TEAD1/4 protein compared to parental NIKS. A series of E6 mutants revealed that E6-mediated degradation of p53 was important for increasing TEAD4 levels. Knockdown of TEADs in NIKS-E6 significantly reduced A3B mRNA levels, whereas ectopic expression of TEAD4 in NIKS increased A3B mRNA levels. Finally, chromatin immunoprecipitation assays demonstrated increased levels of TEAD4 binding to the A3B promoter in NIKS-E6 compared to NIKS. Collectively, these results indicate that E6 induces upregulation of A3B through increased levels of TEADs, highlighting the importance of the TEAD-A3B axis in carcinogenesis.IMPORTANCE The expression of APOBEC3B (A3B), a cellular DNA cytidine deaminase, is upregulated in various human cancers and leaves characteristic, signature mutations in cancer genomes, suggesting that it plays a prominent role in carcinogenesis. Viral oncoproteins encoded by human papillomavirus (HPV) and polyomavirus have been reported to induce A3B expression, implying the involvement of A3B upregulation in virus-associated carcinogenesis. However, the molecular mechanisms causing A3B upregulation remain unclear. Here, we demonstrate that exogenous expression of the cellular transcription factor TEAD activates the A3B promoter. Further, the HPV oncoprotein E6 increases the levels of endogenous TEAD1/4 protein, thereby leading to A3B upregulation. Since increased levels of TEAD4 are frequently observed in many cancers, an understanding of the direct link between TEAD and A3B upregulation is of broad oncological interest.

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Section: Discussionmentioning

confidence: 72%

Human Papillomavirus 16 E6 Upregulates APOBEC3B via the TEAD Transcription Factor

Mori

Takeuchi

Ishii

et al. 2017

J Virol

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“…Recent biochemical and genetic studies have established TEAD as a key downstream mediator of YAP (mammalian homolog of Yki) activity and distribution in Hippo signaling Zhao et al, 2008;Zhang et al, 2009). TEAD1 has also been implicated in prostate and pancreatic cancer (Hucl et al, 2007;Kwon et al, 2007;Knight et al, 2008). .…”

Section: Tead/tef Family Transcriptional Factorsmentioning

confidence: 99%

Structural and functional insights into the TEAD-YAP complex in the Hippo signaling pathway

2010

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The control of organ size growth is one of the most fundamental aspects of life. In the past two decades, a highly conserved Hippo signaling pathway has been identified as a key molecular mechanism for governing organ size regulation. In the middle of this pathway is a kinase cascade that negatively regulates the downstream component Yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ)/Yorkie through phosphorylation. Phosphorylation of YAP/TAZ/Yorkie promotes its cytoplasmic localization, leads to cell apoptosis and restricts organ size overgrowth. When the Hippo pathway is inactivated, YAP/TAZ/Yorkie translocates into the nucleus to bind to the transcription enhancer factor (TEAD/TEF) family of transcriptional factors to promote cell growth and proliferation. In this review, we will focus on the structural and functional studies on the downstream transcription factor TEAD and its coactivator YAP.

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“…CBL is overexpressed in human prostate cancer tissues and increased protein level of CBL was associated with decreased patient survival. 18 Taken together with our finding that CBL is frequently overexpressed in the human breast cancers, it is likely that increased expression of CBL may also be oncogenic. The fact that knockdown of CBL in PC3 prostate cancer cells decreased proliferation is very interesting.…”

Section: Discussionmentioning

confidence: 51%

“…The fact that knockdown of CBL in PC3 prostate cancer cells decreased proliferation is very interesting. 18 It raises an interesting question of whether CBL also functions as a negative regulator of TGF-b signaling in PC3 cells. CBL exerts its functions either through E3 ligase activity or as an adaptor to recruit other molecules.…”

Section: Discussionmentioning

confidence: 99%

“…In myeloid neoplasm and lung cancer, mutations of CBL can induce cancer, 13 --17 and in prostate cancer, the wild-type CBL enhances tumor formation. 18 CBL also functions as an adaptor protein in the signal transduction. CBL and CBL-b contain multiple protein interaction motifs such as the proline-rich regions that bind to SH3 domains of numerous signal-transducing molecules; and tyrosine residues that become phosphorylated and interact with the key SH2 domain-containing signaling proteins.…”

Section: Introductionmentioning

confidence: 99%

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CBL enhances breast tumor formation by inhibiting tumor suppressive activity of TGF-β signaling

et al. 2012

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Casitas B-lineage lymphoma (CBL) protein family functions as multifunctional adaptor proteins and E3 ubiquitin ligases that are implicated as regulators of signaling in various cell types. Recent discovery revealed mutations of proto-oncogenic CBL in the linker region and RING finger domain in human acute myeloid neoplasm, and these transforming mutations induced carcinogenesis. However, the adaptor function of CBL mediated signaling pathway during tumorigenesis has not been well characterized. Here, we show that CBL is highly expressed in breast cancer cells and significantly inhibits transforming growth factor-b (TGF-b) tumor suppressive activity. Knockdown of CBL expression resulted in the increased expression of TGF-b target genes, PAI-I and CDK inhibitors such as p15 INK4b and p21 Cip1 . Furthermore, we demonstrate that CBL is frequently overexpressed in human breast cancer tissues, and the loss of CBL decreases the tumorigenic activity of breast cancer cells in vivo. CBL directly binds to Smad3 through its proline-rich motif, thereby preventing Smad3 from interacting with Smad4 and blocking nuclear translocation of Smad3. CBL-b, one of CBL protein family, also interacted with Smad3 and knockdown of both CBL and CBL-b further enhanced TGF-b transcriptional activity. Our findings provide evidence for a previously undescribed mechanism by which oncogenic CBL can block TGF-b tumor suppressor activity.

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TEAD1 and c-Cbl are novel prostate basal cell markers that correlate with poor clinical outcome in prostate cancer

Cited by 77 publications

References 56 publications

Human Papillomavirus 16 E6 Upregulates APOBEC3B via the TEAD Transcription Factor

Human Papillomavirus 16 E6 Upregulates APOBEC3B via the TEAD Transcription Factor

Structural and functional insights into the TEAD-YAP complex in the Hippo signaling pathway

CBL enhances breast tumor formation by inhibiting tumor suppressive activity of TGF-β signaling

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