ACK1/TNK2 Regulates Histone H4 Tyr88-phosphorylation and AR Gene Expression in Castration-Resistant Prostate Cancer

Mahajan, Kiran; Malla, Pavani; Lawrence, Harshani R.; Chen, Zhihua; Kumar‐Sinha, Chandan; Malik, Rohit; Shukla, Sudhanshu; Kim, Jongphil; Coppola, Domenico; Lawrence, Nicholas J.; Mahajan, Nupam P.

doi:10.1016/j.ccell.2017.05.003

Cited by 97 publications

(128 citation statements)

References 41 publications

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“…Recently, we have reported a new class of robust and soluble TNK2–specific small molecule inhibitor, ( R )- 9b MS [24, 25]. To address the role of TNK2 in AKT Tyr176-phosphorylation in TNBCs, cells were treated with ( R )- 9b MS. A significant decrease in TNK2 activation, as seen by loss of TNK2 Tyr-phosphorylation is observed upon ( R )- 9b MS treatment (Figure 6A).…”

Section: Resultsmentioning

confidence: 99%

The non-receptor tyrosine kinase TNK2/ACK1 is a novel therapeutic target in triple negative breast cancer

Zahari

Renuse

et al. 2016

Oncotarget

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Breast cancer is the most prevalent cancer in women worldwide. About 15-20% of all breast cancers do not express estrogen receptor, progesterone receptor or HER2 receptor and hence are collectively classified as triple negative breast cancer (TNBC). These tumors are often relatively aggressive when compared to other types of breast cancer, and this issue is compounded by the lack of effective targeted therapy. In our previous phosphoproteomic profiling effort, we identified the non-receptor tyrosine kinase TNK2 as activated in a majority of aggressive TNBC cell lines. In the current study, we show that high expression of TNK2 in breast cancer cell lines correlates with high proliferation, invasion and colony forming ability. We demonstrate that knockdown of TNK2 expression can substantially suppress the invasiveness and proliferation advantage of TNBC cells in vitro and tumor formation in xenograft mouse models. Moreover, inhibition of TNK2 with small molecule inhibitor (R)-9bMS significantly compromised TNBC proliferation.Finally, we find that high levels of TNK2 expression in high-grade basal-like breast cancers correlates significantly with poorer patient outcome. Taken together, our study suggests that TNK2 is a novel potential therapeutic target for the treatment of TNBC.

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Section: Resultsmentioning

confidence: 99%

The non-receptor tyrosine kinase TNK2/ACK1 is a novel therapeutic target in triple negative breast cancer

Zahari

Renuse

et al. 2016

Oncotarget

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“…34 A recent study further reported a novel chromatinregulated mechanism of AR transcriptional regulation being mediated by the tyrosine kinase ACK1 (also known as TNK2). 35 ACK1/TNK2 phosphorylates histone H4 at Try88 upstream of the AR transcription start site, leading to WDR5/MLL2 complex-mediated increase of AR transcription, and the epigenetic regulatory circuits drive CRPC progression. Reversal of the pTry88-histone H4 epigenetic marks by the ACK1 inhibitor (R)-9bMS sensitizes naive and ADT-resistant prostate cancer cells and reduces AR expression and halts CRPC growth.…”

Section: Histone Modificationsmentioning

confidence: 99%

“…Reversal of the pTry88-histone H4 epigenetic marks by the ACK1 inhibitor (R)-9bMS sensitizes naive and ADT-resistant prostate cancer cells and reduces AR expression and halts CRPC growth. 35 LSD1 (also known as KDM1A), a FAD-dependent demethylase, functions as a transcriptional repressor of ARregulated enhancers through H3K4 and H3K9 demethylation and as an AR coactivator through interaction with RCOR1/CoREST and phosphorylation of histone H3 Thr-6 (H3T6ph). 36 LSD1 was found to promote CRPC also through epigenetic programming to induce CENPE, a centromere-binding protein and mitotic kinesin, expression.…”

Section: Histone Modificationsmentioning

confidence: 99%

Epigenetic modulations and lineage plasticity in advanced prostate cancer

et al. 2020

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Prostate cancer is the most common cancer and second leading cause of cancer-related death in American men. Antiandrogen therapies are part of the standard of therapeutic regimen for advanced or metastatic prostate cancers; however, patients who receive these treatments are more likely to develop castration-resistant prostate cancer (CRPC) or neuroendocrine prostate cancer (NEPC). In the development of CRPC or NEPC, numerous genetic signaling pathways have been under preclinical investigations and in clinical trials. Accumulated evidence shows that DNA methylation, chromatin integrity, and accessibility for transcriptional regulation still play key roles in prostate cancer initiation and progression. Better understanding of how epigenetic change regulates the progression of prostate cancer and the interaction between epigenetic and genetic modulators driving NEPC may help develop a better risk stratification and more effective treatment regimens for prostate cancer patients.

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“…However, since resistance to ADT has been integrally associated with epigenetic modifications and aberrant tyrosine kinase signaling, development of suitable epigenetic inhibitors likely holds promise for the future in this context. Recent reports have demonstrated the contribution of the non-receptor tyrosine kinase ACK1 in the epigenetic activation of the AR gene locus [43–45]. Targeting ACK1 using an epigenetic inhibitor not only reduced full-length AR levels, but also reduced AR-V7 levels to overcome stemness-associated enzalutamide-resistance, and curb castration-resistant prostate tumor growth [43, 44].…”

Section: Role Of Tumor Plasticity In Neuroendocrine Trans-differentiamentioning

confidence: 99%

EMT, stemness and tumor plasticity in aggressive variant neuroendocrine prostate cancers

Soundararajan

Paranjape

Maity

et al. 2018

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

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Neuroendocrine/Aggressive Variant Prostate Cancers are lethal variants of the disease, with an aggressive clinical course and very short responses to conventional therapy. The age-adjusted incidence rate for this tumor sub-type has steadily increased over the past 20 years in the United States, with no reduction in the associated mortality rate. The molecular networks fueling its emergence and sustenance are still obscure; however, many factors have been associated with the onset and progression of neuroendocrine differentiation in clinically typical adenocarcinomas including loss of androgen-receptor expression and/or signaling, conventional therapy, and dysregulated cytokine function. "Tumor-plasticity" and the ability to dedifferentiate into alternate cell lineages are central to this process. Epithelial-to-mesenchymal (EMT) signaling pathways are major promoters of stem-cell properties in prostate tumor cells. In this review, we examine the contributions of EMT-induced cellular-plasticity and stem-cell signaling pathways to the progression of Neuroendocrine/Aggressive Variant Prostate Cancers in the light of potential therapeutic opportunities.

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ACK1/TNK2 Regulates Histone H4 Tyr88-phosphorylation and AR Gene Expression in Castration-Resistant Prostate Cancer

Cited by 97 publications

References 41 publications

The non-receptor tyrosine kinase TNK2/ACK1 is a novel therapeutic target in triple negative breast cancer

The non-receptor tyrosine kinase TNK2/ACK1 is a novel therapeutic target in triple negative breast cancer

Epigenetic modulations and lineage plasticity in advanced prostate cancer

EMT, stemness and tumor plasticity in aggressive variant neuroendocrine prostate cancers

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