bims-ectoca 2024-02-11 papers

Issue of 2024‒02‒11
four papers selected by
Ankita Daiya, BITS Pilani

Cancer Lett. 2024 Feb 06. pii: S0304-3835(24)00099-5. [Epub ahead of print] 216706

EZH2-mediated development of therapeutic resistance in cancer.

Parminder Kaur, Eswar Shankar, Sanjay Gupta.

Enhancer of zeste homolog 2 (EZH2) regulates gene expression and plays a definite role in cell proliferation, apoptosis, and senescence. Overexpression of EZH2 has been found in various human malignancies, including prostate, breast, and ovarian cancers, and is associated with increased metastasis and poor prognosis. EZH2 catalyzes trimethylation of lysine 27 of histone H3 (H3K27me3) as a canonical role in a PRC2-dependent manner. This mechanism silences various tumor suppressor genes through EZH2-mediated histone lysine methyltransferase activity. As a non-canonical role, EZH2 partners with other signaling molecules to undergo post-translational modification to orchestrate its function as a co-activator playing a critical role in cancer progression. Dysregulation of EZH2 has also been associated with therapeutic resistance in cancer cells. Given the role of EZH2 in promoting carcinogenesis and therapy resistance, both canonical and non-canonical EZH2 inhibitors have been used to combat multiple cancer types. Moreover, combining EZH2 inhibitors with other therapeutic modalities have shown to enhance the therapeutic efficacy and overcome potential resistance mechanisms in these cancerous cells. Therefore, targeting EZH2 through canonical and non-canonical modes appears to be a promising therapeutic strategy to enhance efficacy and overcome resistance in multiple cancers.

Keywords: Chemotherapy resistance; EZH2; EZH2 resistance

DOI: https://doi.org/10.1016/j.canlet.2024.216706

Proc Natl Acad Sci U S A. 2024 Feb 13. 121(7): e2310430121

Phase separation of YAP-MAML2 differentially regulates the transcriptome.

Chan-I Chung, Junjiao Yang, Xiaoyu Yang, Hongjiang Liu, Zhimin Ma, Frank Szulzewsky, Eric C Holland, Yin Shen, Xiaokun Shu.

Phase separation (PS) drives the formation of biomolecular condensates that are emerging biological structures involved in diverse cellular processes. Recent studies have unveiled PS-induced formation of several transcriptional factor (TF) condensates that are transcriptionally active, but how strongly PS promotes gene activation remains unclear. Here, we show that the oncogenic TF fusion Yes-associated protein 1-Mastermind like transcriptional coactivator 2 (YAP-MAML2) undergoes PS and forms liquid-like condensates that bear the hallmarks of transcriptional activity. Furthermore, we examined the contribution of PS to YAP-MAML2-mediated gene expression by developing a chemogenetic tool that dissolves TF condensates, allowing us to compare phase-separated and non-phase-separated conditions at identical YAP-MAML2 protein levels. We found that a small fraction of YAP-MAML2-regulated genes is further affected by PS, which include the canonical YAP target genes CTGF and CYR61, and other oncogenes. On the other hand, majority of YAP-MAML2-regulated genes are not affected by PS, highlighting that transcription can be activated effectively by diffuse complexes of TFs with the transcriptional machinery. Our work opens new directions in understanding the role of PS in selective modulation of gene expression, suggesting differential roles of PS in biological processes.

DOI: https://doi.org/10.1073/pnas.2310430121

Mol Ther. 2024 Feb 06. pii: S1525-0016(24)00072-8. [Epub ahead of print]

Metabolic Reprogramming Directed by Super-enhancers in Tumors: An Emerging Landscape.

Zongjiang Zhou, Jinghe Li, Diabate Ousmane, Li Peng, Xiaoqing Yuan, Junpu Wang.

Metabolic reprogramming is an essential hallmark of tumors, and metabolic abnormalities are strongly associated with the malignant phenotype of tumor cells. This is closely related to transcriptional dysregulation. Super-enhancers are extremely active cis-regulatory regions in the genome, and can amalgamate a complex set of transcriptional regulatory components that are crucial for establishing tumor cell identity, promoting tumorigenesis, and enhancing aggressiveness. In addition, alterations in metabolic signaling pathways are often accompanied by changes in super-enhancers. Presently, there is a surge in interest in the potential pathogenesis of various tumors through transcriptional regulation of super-enhancers and oncogenic mutations in super-enhancers. In this review, we summarize the functions of super-enhancers, oncogenic signaling pathways, and tumor metabolic reprogramming. In particular, we focus on the role of the super-enhancer in tumor metabolism and its impact on metabolic reprogramming. This review also discusses the prospects and directions in the field of super-enhancer and metabolic reprogramming.

Keywords: metabolic reprogramming; oncogene; signaling pathway; super-enhancer; tumor

DOI: https://doi.org/10.1016/j.ymthe.2024.02.003

Cancer Metastasis Rev. 2024 Feb 08.

Cancer cell plasticity: from cellular, molecular, and genetic mechanisms to tumor heterogeneity and drug resistance.

Gh Rasool Bhat, Itty Sethi, Hana Q Sadida, Bilal Rah, Rashid Mir, Naseh Algehainy, Ibrahim Altedlawi Albalawi, Tariq Masoodi, Gowtham Kumar Subbaraj, Farrukh Jamal, Mayank Singh, Rakesh Kumar, Muzafar A Macha, Shahab Uddin, Ammira S Al-Shabeeb Akil, Mohammad Haris, Ajaz A Bhat.

Cancer is a complex disease displaying a variety of cell states and phenotypes. This diversity, known as cancer cell plasticity, confers cancer cells the ability to change in response to their environment, leading to increased tumor diversity and drug resistance. This review explores the intricate landscape of cancer cell plasticity, offering a deep dive into the cellular, molecular, and genetic mechanisms that underlie this phenomenon. Cancer cell plasticity is intertwined with processes such as epithelial-mesenchymal transition and the acquisition of stem cell-like features. These processes are pivotal in the development and progression of tumors, contributing to the multifaceted nature of cancer and the challenges associated with its treatment. Despite significant advancements in targeted therapies, cancer cell adaptability and subsequent therapy-induced resistance remain persistent obstacles in achieving consistent, successful cancer treatment outcomes. Our review delves into the array of mechanisms cancer cells exploit to maintain plasticity, including epigenetic modifications, alterations in signaling pathways, and environmental interactions. We discuss strategies to counteract cancer cell plasticity, such as targeting specific cellular pathways and employing combination therapies. These strategies promise to enhance the efficacy of cancer treatments and mitigate therapy resistance. In conclusion, this review offers a holistic, detailed exploration of cancer cell plasticity, aiming to bolster the understanding and approach toward tackling the challenges posed by tumor heterogeneity and drug resistance. As articulated in this review, the delineation of cellular, molecular, and genetic mechanisms underlying tumor heterogeneity and drug resistance seeks to contribute substantially to the progress in cancer therapeutics and the advancement of precision medicine, ultimately enhancing the prospects for effective cancer treatment and patient outcomes.

Keywords: Cancer cell plasticity; Cancer stem cells; Drug resistance; Epithelial-mesenchymal transition; Targeted therapies; Tumor heterogeneity

DOI: https://doi.org/10.1007/s10555-024-10172-z