Biology subjects

Kasinski, A. L.

Publications and source records attributed to Kasinski, A. L..

5 recordsLinked to original sources

bioRxiv2026

KMT5C-H4K20me3 drives changes in epigenetic landscape independent of H3K9me3

Histone H4 lysine 20 trimethylation (H4K20me3) is a histone modification that is critical in maintaining genome integrity. Dysregulation of H4K20me3 and KMT5C, the major methyltransferase for H4K20me3, occurs commonly in multiple types of cancer but the mechanisms surrounding how they contribute to shaping the epigenomic landscape remains unclear. Here, we show that KMT5C is involved in non-canonical deposition of H4K20me3, independent of H3K9me3, which was previously recognized as a prerequisite for H4K20me3. This novel subtype of H4K20me3 lacks canonical repressive epigenetic signatures and instead overlaps with multiple activating marks. These activating modifications likely contribute to the dynamic changes in transcript levels upon loss of H4K20me3. The mechanism involved in recruiting KMT5C to these loci is independent of HP1, the factor reported to be involved in recruitment of KMT5C to heterochromatin marked with H3K9me3. Instead, biochemical analyses revealed ZNF280C to be a novel interacting partner of KMT5C, with ZNF280C localizing specifically at H3K9me3-/H4K20me3+ sites. Together, these results suggest a novel, non-canonical function of KMT5C-H4K20me3 that protects vulnerable regions of the genome from uncontrolled expression.

genomics↗

bioRxiv2026

Exosome-like biogenesis from the Golgi releases extracellular vesicles lacking conventional tetraspanins that mediate immune evasion in cancer

Immunotherapy has improved survival across multiple malignancies but remains largely ineffective in solid cancers such as lung, breast, and pancreatic cancer. A key driver of resistance is the immunosuppressive tumor microenvironment (TME). Although numerous mediators of TME immunosuppression have been identified, therapeutic targeting has provided limited clinical benefit. Tumor-derived extracellular vesicles (EVs) have recently emerged as contributors to resistance, yet their mechanisms remain unclear. We developed human non-small cell lung cancer models to investigate EV-mediated immunosuppression. We identified a distinct Golgi-derived EV subpopulation that potently suppress T cell function and tumor infiltration. These EVs express the trans-Golgi network marker TGOLN2, and exhibit minimal levels of canonical EV markers. TGOLN2 overexpression drives this suppressive phenotype. Clinically, elevated TGOLN2 associates with poor survival and correlate with an immunosuppressive TME signature across more than 20 cancer types, including NSCLC. Collectively, this work defines a previously unrecognized mechanism of TGOLN2-driven, EV-mediated immunosuppression. Statement of SignificanceWe revealed TGOLN2 overexpression as a new immune evasion mechanism that mediates T cell suppression through increased secretion of a Golgi-derived extracellular vesicle (EV) subpopulation. These findings redefine current paradigms of EV biology and nominate TGOLN2 as a potential biomarker and therapeutic target in immunosuppressive cancers.

cell biology↗

bioRxiv2023

Developing folate-conjugated miR-34a therapeutic for prostate cancer treatment: Challenges and promises

Prostate cancer (PCa) remains a common cancer with high mortality in men due to its heterogeneity and the emergence of drug resistance. A critical factor contributing to its lethality is the presence of prostate cancer stem cells (PCSCs), which can self-renew, long-term propagate tumors and mediate treatment resistance. MicroRNA-34a (miR-34a) has shown promise as an anti-PCSC therapeutic by targeting critical molecules involved in cancer stem cell (CSC) survival and functions. Despite extensive efforts, the development of miR-34a therapeutics still faces challenges, including non-specific delivery and delivery-associated toxicity. One emerging delivery approach is ligand-mediated conjugation, aiming to achieve specific delivery of miR-34a to cancer cells, thereby enhancing efficacy while minimizing toxicity. Folate-conjugated miR-34a (folate-miR-34a) has demonstrated promising anti-tumor efficacy in breast and lung cancers by targeting folate receptor (FOLR1). Here, we first show that miR-34a, a TP53 transcriptional target, is reduced in PCa that harbors TP53 loss or mutations and that miR-34a mimic, when transfected into PCa cells, downregulated multiple miR-34a targets and inhibited cell growth. When exploring the therapeutic potential of folate-miR-34a, we found that folate-miR-34a exhibited impressive inhibitory effects on breast, ovarian and cervical cancer cells but showed minimal effects on and targeted delivery to PCa cells due to a lack of appreciable expression of FOLR1 in PCa cells. Folate-miR-34a also did not display any apparent effect on PCa cells expressing prostate-specific membrane antigen (PMSA) despite the reported folates binding capability to PSMA. These results highlight challenges in specific delivery of folate-miR-34a to PCa due to lack of target (receptor) expression. Our study offers novel insights on the challenges and promises within the field and cast light on the development of ligand-conjugated miR-34a therapeutics for PCa.

cancer biology↗

bioRxiv2020

Loss of SUV420H2 promotes EGFR inhibitor resistance in NSCLC through upregulation of MET via LINC01510

Epidermal growth factor receptor inhibitors (EGFRi) are standard-of-care treatments administered to patients with non-small cell lung cancer (NSCLC) that harbor EGFR alterations. However, development of resistance within a year post-treatment remains a major challenge. Multiple mechanisms can promote survival of EGFRi treated NSCLC cells, including secondary mutations in EGFR and activation of bypass tracks that circumvent the requirement for EGFR signaling. Nevertheless, mechanisms involved in bypass track activation are understudied, and in a subset of cases the mechanisms are unknown. The findings from this study identified an epigenetic factor, SUV420H2 that when lost drives resistance of NSCLC to multiple EGFRi, including erlotinib, gefitinib, afatinib, and osimertinib. SUV420H2 catalyzes trimethylation of histone H4 lysine-20, a modification required for gene repression and maintenance of heterochromatin. Here we show that loss of SUV420H2 leads to upregulation of an oncogenic long non-coding RNA, LINC01510 that promotes transcription of the oncogene MET, a component of a major bypass track involved in EGFRi resistance. SignificanceDue to an incomplete understanding of the mechanisms involved in promoting resistance to EGFRi, patients often succumb to their disease. Here we identified a global mediator of EGFRi resistance, SUV420H2 that helps to uncover an additional mechanism involved in resistance driven via a major bypass track involving the protooncogene MET.

cancer biology↗

bioRxiv2018

Enhancing microRNA activity through increased endosomal release mediated by nigericin

The therapeutic promise of small RNA therapeutics (siRNAs, miRNAs) is not only limited by the lack of delivery vehicles, but also by the inability of the small RNAs to reach intracellular compartments where they can be biologically active. We previously reported successful delivery of functionally active miRNAs via receptor-mediated endocytosis1. This type of targeted therapy still faces one of the major challenges in the delivery field, endosomal sequestration. Here, a new method has been developed to promote endosomal escape of delivered miRNA. The strategy relies on the difference in solute contents between nascent endosomes and the cytoplasm: early endosomes are rich in sodium ions (Na+) while the intracellular fluid is rich is potassium ions (K+). Exploiting this difference through favoring the influx of K+ into the endosomes without the exchange for a osmotically active ion (Na+), results in an osmotic differential leading to endosome swelling and bursting. One molecule that is able to exchange K+ for an osmotically inactive hydrogen ion is the ionophore nigericin. Via generating an intramolecular miRNA delivery vehicle, containing a ligand, in this case folate, and nigericin we achieve escape of folate-RNA conjugates (e.g. FolamiRs) from their entrapping endosomes into the cytoplasm where they bind the RNA Induced Silencing complex (RISC) and activate the RNAi response.

molecular biology↗