Human WDR5 promotes breast cancer growth and metastasis via KMT2-independent translation regulation
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Evaluation Summary:
The authors of this manuscript, which is of interest to the cancer community, identify the chromatin regulator WDR5 as a possible new drug target in triple negative breast cancer. Targeted therapeutics for this patient population are of high scientific and clinical interest, and the authors provide a compelling case that co-targeting WDR5 along with mTOR provides a promising new therapeutic strategy.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 and Reviewer #2 agreed to share their names with the authors.)
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Abstract
Metastatic breast cancer remains a major cause of cancer-related deaths in women, and there are few effective therapies against this advanced disease. Emerging evidence suggests that key steps of tumor progression and metastasis are controlled by reversible epigenetic mechanisms. Using an in vivo genetic screen, we identified WDR5 as an actionable epigenetic regulator that is required for metastatic progression in models of triple-negative breast cancer. We found that knockdown of WDR5 in breast cancer cells independently impaired their tumorigenic as well as metastatic capabilities. Mechanistically, WDR5 promotes cell growth by increasing ribosomal gene expression and translation efficiency in a KMT2-independent manner. Consistently, pharmacological inhibition or degradation of WDR5 impedes cellular translation rate and the clonogenic ability of breast cancer cells. Furthermore, a combination of WDR5 targeting with mTOR inhibitors leads to potent suppression of translation and proliferation of breast cancer cells. These results reveal novel therapeutic strategies to treat metastatic breast cancer.
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Evaluation Summary:
The authors of this manuscript, which is of interest to the cancer community, identify the chromatin regulator WDR5 as a possible new drug target in triple negative breast cancer. Targeted therapeutics for this patient population are of high scientific and clinical interest, and the authors provide a compelling case that co-targeting WDR5 along with mTOR provides a promising new therapeutic strategy.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 and Reviewer #2 agreed to share their names with the authors.)
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Reviewer #1 (Public Review):
In this work, Cai et al identified WDR5 as an important and druggable chromatin regulator involved in metastatic progression of triple-negative breast cancer (TNBC) through an in vitro and in vivo genetic screening. The authors further studied the underlying mechanisms and found that WDR5 promotes TNBC cell growth by positively regulating the ribosome gene expression and therefore the translation efficiency in cancer cells. Interestingly, this regulation by WDR5 is independent of MLL/KMT2 complex in their breast cancer models. Pharmacological inhibition by WDR5 inhibitor or WDR5 degrader showed the decreased clonogenic ability, reminiscent of genetic knockdown of WDR5, in the breast cancer models. Finally, the authors provided a potential therapeutic strategy for the treatment of metastatic breast cancers by …
Reviewer #1 (Public Review):
In this work, Cai et al identified WDR5 as an important and druggable chromatin regulator involved in metastatic progression of triple-negative breast cancer (TNBC) through an in vitro and in vivo genetic screening. The authors further studied the underlying mechanisms and found that WDR5 promotes TNBC cell growth by positively regulating the ribosome gene expression and therefore the translation efficiency in cancer cells. Interestingly, this regulation by WDR5 is independent of MLL/KMT2 complex in their breast cancer models. Pharmacological inhibition by WDR5 inhibitor or WDR5 degrader showed the decreased clonogenic ability, reminiscent of genetic knockdown of WDR5, in the breast cancer models. Finally, the authors provided a potential therapeutic strategy for the treatment of metastatic breast cancers by combinational WDR5 and mTOR inhibition.
Overall, this study is well designed, comprehensive and well done.
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Reviewer #2 (Public Review):
The study by Cai et al. sought to identify novel actionable candidates towards the development of therapeutic treatments for metastatic triple negative breast cancer (TNBC), a subtype with poor prognosis. The authors performed inducible knockdown of a focussed library of 69 candidate epigenetic regulators using a cell model of lung-metastatic TNBC (MDA-MB-231-LM2 cells), using both in vitro (cell proliferation) and in vivo (xenograft lung metastasis) screens. This identified several candidate genes including WDR5, whose depletion was found to limit TNBC tumour growth and metastasis in both models. The requirement for functional WDR5 was further validated across other BCa cell lines using shRNA knockdown, or pharmacological inhibition/degradation of WDR5 in a range of standard assays. Transcriptome profiling …
Reviewer #2 (Public Review):
The study by Cai et al. sought to identify novel actionable candidates towards the development of therapeutic treatments for metastatic triple negative breast cancer (TNBC), a subtype with poor prognosis. The authors performed inducible knockdown of a focussed library of 69 candidate epigenetic regulators using a cell model of lung-metastatic TNBC (MDA-MB-231-LM2 cells), using both in vitro (cell proliferation) and in vivo (xenograft lung metastasis) screens. This identified several candidate genes including WDR5, whose depletion was found to limit TNBC tumour growth and metastasis in both models. The requirement for functional WDR5 was further validated across other BCa cell lines using shRNA knockdown, or pharmacological inhibition/degradation of WDR5 in a range of standard assays. Transcriptome profiling revealed that depletion of WDR5 reduced global translation efficiency and specifically impacted expression of ribosomal proteins, suggesting a mechanism for its role in promoting TNBC. Rescue experiments using WT and mutant WDR5 proteins revealed that recruitment of the canonical KMT2 complexes via the WIN domain is not critical for breast cancer cell growth or ribosomal gene expression, and this was supported by shRNA knockdown of individual components of the KMT2A/B, SET1A and SET1B complexes. In contrast, WDR5 proteins carrying substitution mutations in the WBM domain (involved in binding to cMYC and RBBP5) failed to efficiently rescue growth phenotype and ribosomal gene expression. It was shown that these mutants retained the ability to be recruited to ribosomal gene promoters, and had little effect on H3K4me3 levels, thus the mechanism requires further investigation. Finally, the effects of WDR5 alone or in combination with MTOR pathway inhibitors was assessed. The overall conclusions here were that MTOR and WDR5 are likely to promote protein synthesis via distinct mechanisms and that targeting both pathways had at least additive effects. Moreover, inhibitors that target both mTORC1 and mTORC2 were more effective than everolimus when combined with WDR5 depletion.
Strengths: Overall the study is very thorough and well-executed with appropriate controls and validatory experiments. The data are convincing and clearly presented, and generally support the conclusions. The use of parallel complementary screens is a strength, as is inclusion of other cell lines and subtypes to support the model.
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