SHH-N Non-Canonically Sustains Androgen Receptor Activity in Androgen-Independent Prostate Cancer Cells

Researchers investigated the role of Hedgehog-GLI signaling in sustaining androgen-independent growth of prostate cancer cells.
[Scientific Reports]
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PGE2-JNK Signaling Axis Non-Canonically Promotes Gli Activation by Protecting Gli2 from Ubiquitin-Proteasomal Degradation

Colorectal cancer cells hijacked prostaglandin E2 (PGE2) to non-canonically promote Hedgehog transcriptional factor Gli activity and Gli-dependent proliferation of colorectal cancer cells in a Smo-independent manner.
[Cell Death & Disease]
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Smoothened Inhibition Leads to Decreased Cell Proliferation and Suppressed Tissue Fibrosis in the Development of Benign Prostatic Hyperplasia

Scientists revealed that the smoothened cascade was upregulated in benign prostatic hyperplasia tissues and was localized in both the stromal and the epithelium compartments of human prostate tissues.
[Cell Death Discovery]
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Targeting Non-Canonical Activation of GLI1 by the SOX2-BRD4 Transcriptional Complex Improves the Efficacy of HEDGEHOG Pathway Inhibition in Melanoma

Researchers identified a novel SOX2-BRD4 transcriptional complex driving the expression of GLI1, the final effector of the Hedgehog/GLI (HH/GLI) pathway, providing a novel mechanism of non-canonical Smoothened-independent activation of HH/GLI signaling in melanoma.
[Oncogene]
Pietrobono, S., Gaudio, E., Gagliardi, S., Zitani, M., Carrassa, L., Migliorini, F., Petricci, E., Manetti, F., Makukhin, N., Bond, A. G., Paradise, B. D., Ciulli, A., Fernandez-Zapico, M. E., Bertoni, F., & Stecca, B. (2021). Targeting non-canonical activation of GLI1 by the SOX2-BRD4 transcriptional complex improves the efficacy of HEDGEHOG pathway inhibition in melanoma. Oncogene, 1–16. https://doi.org/10.1038/s41388-021-01783-9 Cite
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Smoothened Loss Is a Characteristic of Neuroendocrine Prostate Cancer

Scientists assessed the expression of key genes involved in hedgehog signaling in prostate cancer and investigated the potential role of smoothened in the pathogenesis of neuroendocrine prostate cancer.
[Prostate]
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CD47-Mediated Hedgehog/SMO/GLI1 Signaling Promotes Mesenchymal Stem Cell Immunomodulation in Mouse Liver Inflammation

Investigators found that mesenchymal stem cell CD47 and macrophage signal regulatory protein alpha expression were increased after LPS stimulation.
[Hepatology]
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Inhibition of Melanoma Cell Migration and Invasion Targeting the Hypoxic Tumor Associated CAXII

Researchers demonstrated that malignant melanoma cell motility was impaired by targeting carbonic anhydrase IX via either carbonic anhydrase inhibitors or through the inhibition of the Hedgehog pathway.
[Cancers]
Giuntini, G., Monaci, S., Cau, Y., Mori, M., Naldini, A., & Carraro, F. (2020). Inhibition of Melanoma Cell Migration and Invasion Targeting the Hypoxic Tumor Associated CAXII. Cancers, 12(10), 3018. https://doi.org/10.3390/cancers12103018 Cite
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AP-1 and TGFß Cooperativity Drives Non-Canonical Hedgehog Signaling in Resistant Basal Cell Carcinoma

The authors used single cell RNA-sequencing of patient tumors to identify three prognostic surface markers (LYPD3, TACSTD2, and LY6D) which correlated with myocardin-related transcription factor (nMRTF) and resistance to Smoothened inhibitors. The nMRTF cell state resembled transit-amplifying cells of the hair follicle matrix, with AP-1 and TGFß cooperativity driving nMRTF activation.
[Nature Communications]
Yao, C. D., Haensel, D., Gaddam, S., Patel, T., Atwood, S. X., Sarin, K. Y., Whitson, R. J., McKellar, S., Shankar, G., Aasi, S., Rieger, K., & Oro, A. E. (2020). AP-1 and TGFß cooperativity drives non-canonical Hedgehog signaling in resistant basal cell carcinoma. Nature Communications, 11(1), 5079. https://doi.org/10.1038/s41467-020-18762-5 Cite
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The Role of Smoothened in Cancer

Smoothened (SMO) expression correlates with tumor size, invasiveness, metastasis and recurrence. In addition, SMO inhibitors can suppress cancer formation, reduce the proliferation of cancer cells, trigger apoptosis and suppress cancer stem cell activity.
[International Journal of Medical Sciences]
Jeng, K.-S., Sheen, I.-S., Leu, C.-M., Tseng, P.-H., & Chang, C.-F. (2020). The Role of Smoothened in Cancer. International Journal of Molecular Sciences, 21(18), 6863. https://doi.org/10.3390/ijms21186863 Cite
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Combined Inhibition of JAK2-STAT3 and SMO-GLI1/tGLI1 Pathways Suppresses Breast Cancer Stem Cells, Tumor Growth, and Metastasis

Investigators showed that novel combinations of JAK2 inhibitors with SMO inhibitors synergistically inhibited in vitro growth of TNBC and HER2-positive trastuzumab-resistant BT474-TtzmR cells.
[Oncogene]
Doheny, D., Sirkisoon, S., Carpenter, R. L., Aguayo, N. R., Regua, A. T., Anguelov, M., Manore, S. G., Arrigo, A., Jalboush, S. A., Wong, G. L., Yu, Y., Wagner, C. J., Chan, M., Ruiz, J., Thomas, A., Strowd, R., Lin, J., & Lo, H.-W. (2020). Combined inhibition of JAK2-STAT3 and SMO-GLI1/tGLI1 pathways suppresses breast cancer stem cells, tumor growth, and metastasis. Oncogene, 1–17. https://doi.org/10.1038/s41388-020-01454-1 Cite
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Garcinone C Suppresses Colon Tumorigenesis through the Gli1-dependent Hedgehog Signaling Pathway

Colony formation assay and flow cytometry were used to evaluate the effect of garcinone C on the proliferation and cell cycle progression of colon cancer cells.
[Phytomedicine]
Chen, J., Qiu, S., Kim, J. T., Cho, J. S., Moon, J. H., Zhou, Y., Auh, J.-H., & Lee, H. J. (2020). Garcinone C Suppresses Colon Tumorigenesis Through the Gli1-dependent Hedgehog Signaling Pathway. Phytomedicine, 153334. https://doi.org/10.1016/j.phymed.2020.153334 Cite
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