Biology subjects

Hakkola, S.

Publications and source records attributed to Hakkola, S..

3 recordsLinked to original sources

bioRxiv2026

PGM3 inhibition rewires RUVBL2-dependent DNA repair and induces a BRCAness-like state in pancreatic cancer cells

Pancreatic ductal adenocarcinoma (PDAC) exhibits profound metabolic rewiring and strong resistance to DNA-damaging therapies, yet how metabolic pathways regulate genome maintenance remains poorly understood. The hexosamine biosynthetic pathway (HBP) integrates nutrient availability with protein glycosylation through production of UDP-GlcNAc, but its role in DNA damage response (DDR) regulation is unclear. Here we show that inhibition of the HBP enzyme phosphoglucomutase-3 (PGM3) reduces DNA repair capacity in pancreatic cancer cells. Transcriptomic and functional analyses reveal that the selective PGM3 inhibitor FR054 amplifies gemcitabine-induced replication stress, disrupts ATR-CHK1 and ATM-CHK2 checkpoint signaling, and selectively impairs homologous recombination. Glycoproteomic profiling identifies the AAA+ ATPase RUVBL2 as a key metabolic-DDR node. Gemcitabine increases RUVBL2 O-GlcNAcylation, with Thr81 identified as a modified residue within the Walker A nucleotide-binding motif. Structural modelling predicts that Thr81 O-GlcNAcylation stabilizes the RUVBL1-RUVBL2 complex without compromising ATP-Mg engagement. PGM3 inhibition and Thr81 mutation similarly reduced ATR and ATM abundance and promoted persistent DNA damage, supporting a role for RUVBL2 Thr81 O-GlcNAcylation in sustaining checkpoint signalling and genome stability. Consequently, PGM3 inhibition induces a BRCAness-like state that sensitizes pancreatic cancer cells to PARP inhibition, both in vitro and in vivo, as well as to ionizing radiation. These findings reveal a nutrient-sensitive mechanism linking protein glycosylation to genome maintenance and identify HBP-dependent DNA repair as a potentially actionable vulnerability in pancreatic cancer.

cancer biology↗

bioRxiv2026

AR suppression rewires a SOX4 regulatory program to promote enzalutamide resistance in prostate cancer

Treatment resistance in prostate cancer remains a major clinical challenge. While single-cell transcriptomics enables mapping of cellular composition and resistance-associated states, the gene regulatory programs driving these state transitions remain poorly defined. Here, we integrate single-cell chromatin accessibility and transcriptome sequencing data from an in vitro model to resolve the regulatory program architecture underlying anti-androgen resistance. We identify coordinated remodeling of androgen signaling- and stress response-associated regulatory programs, together with a pronounced gain of a SOX4-driven regulatory program in resistant cells. Analysis of clinical datasets reveals that SOX4 activity is both context-dependent and lineage-specific. In primary tumors, SOX4 cis-regulatory activity is elevated in PTEN-loss tumors, consistent with a PTEN-PI3K/AKT/mTOR-SOX4 axis that primes AR-independent epithelial lineages for subsequent activation of a more extensive SOX4 trans-regulatory program. This program is further amplified following AR-targeted therapy, indicating therapy-induced reinforcement of SOX4-linked regulatory adaptation. TF footprinting additionally implicates Nuclear Factor I family transcription factors as upstream regulators of SOX4, supporting a role in promoting SOX4 activation following AR inhibition. Together, these findings demonstrate that AR inhibition reshapes the gene regulatory landscape to promote engagement of the SOX4 program, facilitating prostate cancer progression under anti-androgen therapy.

cancer biology↗

bioRxiv2026

Deep Invaginations of Nuclear Envelope Coordinate Spatial Organization of Chromatin in Epithelium

Cell nuclei are often used to assess cell health, but how their shapes vary in normal tissues and how they respond to mechanical forces is not well understood. Here, we describe deep invaginations of the nuclear envelope (DINEs) as common features of epithelial cell nuclei. After their formation, DINEs exist independently of the cytoskeleton, depend on A-type lamins, and emerge in response to cell crowding, contact inhibition, and tissue maturation. High-resolution imaging shows that, in contrast to the peripheral nuclear lamina, DINEs contain densely packed chromatin with regions of active gene transcription. They also remodel dynamically during confined migration, allowing nuclei to adapt to physical constraints. Mechanistically, DINE formation is linked to suppression of MAPK signaling, while activation of growth-promoting pathways reduces their occurrence. These findings reveal DINEs as intrinsic, mechanosensitive structures that coordinate nuclear shape, chromatin organization, and gene activity, providing new insight into how epithelial cells integrate mechanical and biochemical cues to maintain tissue homeostasis. TeaserDeep nuclear envelope invaginations organize chromatin and gene activity in response to epithelial crowding.

cell biology↗