Biology subjects

Flores, N. M.

Publications and source records attributed to Flores, N. M..

4 recordsLinked to original sources

bioRxiv2025

SETD2 suppresses tumorigenesis in a KRASG12C-driven lung cancer model and its catalytic activity is regulated by histone acetylation

Histone H3 trimethylation at lysine 36 (H3K36me3) is a key chromatin modification that regulates fundamental physiologic and pathologic processes. In humans, SETD2 is the only known enzyme that catalyzes H3K36me3 in somatic cells and is implicated in tumor suppression across multiple cancer types. While there is considerable crosstalk between the SETD2-H3K36me3 axis and other epigenetic modifications, much remains to be understood. Here, we show that SETD2 functions as a potent tumor suppressor in a KRASG12C-driven lung adenocarcinoma (LUAD) mouse model, and that acetylation enhances SETD2 in vitro methylation of H3K36 on nucleosome substrates. In vivo, SETD2 ablation accelerates lethality in an autochthonous KRASG12C-driven LUAD mouse tumor model. Biochemical analyses reveal that polyacetylation of histone tails in a nucleosome context promote H3K36 methylation by SETD2. In addition, monoacetylation exerts position-specific effects to stimulate SETD2 methylation activity. In contrast, mono-ubiquitination at various histone sites, including at H2AK119 and H2BK120, does not affect SETD2 methylation of nucleosomes. Together, these findings provide insight into how SETD2 integrates histone modification signals to regulate H3K36 methylation and highlights the potential role of SETD2-associated epigenetic crosstalk in cancer pathogenesis.

molecular biology↗

bioRxiv2024

Planarians Develop Radiotolerance to Recurrent Ionizing Radiation Exposure

Exposure to ionizing radiation can induce DNA fragmentation, leading to double-strand breaks, the most toxic form of DNA damage. Some organisms have developed mechanisms to overcome the adverse effects of ionizing radiation by enhancing DNA protection and repair. However, the underlying mechanisms driving radiation resistance to maintain genomic integrity and function remain poorly understood. Here, we provide evidence for the development of radiotolerance in the flatworm planarian Schmidtea mediterranea. We implemented a strategy to select animals capable of overcoming repeated rounds of ionizing radiation exposure. We demonstrate that planarians initially exposed to higher amounts of sub-lethal radiation can adapt, gaining the ability to recover reproductive capabilities faster than animals initially exposed to lower amounts of sub-lethal radiation. Our findings show that DNA integrity is reestablished in about one week after five cycles of sub-lethal ionizing radiation exposure. Planarian stem cells, known as neoblasts, can repair repeated DNA double-strand breaks by activating Rad51-mediated homologous recombination. The expression of the neoblast marker smedpiwi-1 and the mitotic activity reach levels similar to unirradiated animals between two and three weeks post-radiation. We describe that planarians develop radiotolerance through recurrent ionizing radiation exposure over several years and survive without apparent functional or morphological defects for an undetermined time.

developmental biology↗

bioRxiv2024

SMYD5 is a ribosomal methyltransferase that catalyzes RPL40 lysine methylation to enhance translation output and promote hepatocellular carcinoma

While lysine methylation is well-known for regulating gene expression transcriptionally, its implications in translation have been largely uncharted. Trimethylation at lysine 22 (K22me3) on RPL40, a core ribosomal protein located in the GTPase activation center (GAC), was first reported 27 years ago. Yet, its methyltransferase and role in translation remain unexplored. Here, we report that SMYD5 has robust in vitro activity toward RPL40 K22 and primarily catalyzes RPL40 K22me3 in cells. The loss of SMYD5 and RPL40 K22me3 leads to reduced translation output and disturbed elongation as evidenced by increased ribosome collisions. SMYD5 and RPL40 K22me3 are upregulated in hepatocellular carcinoma (HCC) and negatively correlated with patient prognosis. Depleting SMYD5 renders HCC cells hypersensitivity to mTOR inhibition in both 2D and 3D cultures. Additionally, the loss of SMYD5 markedly inhibits HCC development and growth in both genetically engineered mouse (GEM) and patient-derived xenograft (PDX) models, with the inhibitory effect in the PDX model further enhanced by concurrent mTOR suppression. Our findings reveal a novel role of the SMYD5 and RPL40 K22me3 axis in translation elongation and highlight the therapeutic potential of targeting SMYD5 in HCC, particularly with concurrent mTOR inhibition. This work also broadens the understanding of lysine methylation, extending its significance from transcriptional regulation to translational control.

cancer biology↗

bioRxiv2023

Cytoskeleton remodeling induced by SMYD2 methyltransferase drives breast cancer metastasis

Malignant forms of breast cancer refractory to existing therapies remain a major unmet health issue, primarily due to metastatic spread. A better understanding of the mechanisms at play will provide better insights for alternative treatments to prevent breast cancer cells dispersion. Here, we identify the lysine methyltransferase SMYD2 as a clinically actionable master regulator of breast cancer metastasis. While SMYD2 is overexpressed in aggressive breast cancers, we notice that it is not required for primary tumor growth. However, mammary-epithelium specific SMYD2 ablation increases mouse overall survival by blocking the primary tumor cells ability to metastasize. Mechanistically, we identify BCAR3 as a genuine physiological substrate of SMYD2 in breast cancer cells. BCAR3 monomethylated at lysine K334 (K334me1) is recognized by a novel methyl-binding domain present in FMNLs proteins. These actin cytoskeleton regulators are recruited at the cell edges by the SMYD2 methylation signaling and modulates lamellipodia properties. Breast cancer cells with impaired BCAR3 methylation loose migration and invasiveness capacity in vitro and are ineffective in promoting metastases in vivo. Remarkably, SMYD2 pharmacologic inhibition efficiently impairs the metastatic spread of breast cancer cells, PDX and aggressive mammary tumors from genetically engineered mice. This study provides a rationale for innovative therapeutic prevention of malignant breast cancer metastatic progression by targeting the SMYD2-BCAR3-FMNL axis.

cancer biology↗