Hailing Cheng

Targeting ZDHHC12-mediated PARP1 palmitoylation potentiates PARP inhibitor cytotoxicity

Poly(ADP-ribose) polymerase inhibitors (PARPi) elicit cytotoxicity by trapping PARP1 at DNA lesions, but clinical resistance remains a major challenge. Here, we identify reversible S-palmitoylation as a negative regulator of PARP1 chromatin engagement. Mass spectrometry reveals PARP1 palmitoylation at conserved cysteines within its DNA-binding domains. DNA damage reduces PARP1 palmitoylation, enhancing DNA binding, whereas inhibition of depalmitoylases APT1/2 elevates palmitoylation and suppresses DNA binding. The palmitoyltransferase ZDHHC12 catalyzes PARP1 palmitoylation, and its inhibition, along with the blockade of palmitate synthesis or global palmitoylation, augments PARP1 trapping and sensitizes high-grade ovarian cancer (HGSOC) cells to the PARPi Niraparib. Patient-derived PARP1 variants R138C and R591C display hyper-palmitoylation, impaired trapping, and PARPi resistance through an indirect mechanism independent of palmitoylation at the mutation sites. ZDHHC12 knockdown restores PARP1 trapping and resensitizes resistant cells and xenografts to Niraparib. These findings establish ZDHHC12-mediated PARP1 palmitoylation as a targetable vulnerability to overcome PARPi resistance.

SGK1 suppresses ferroptosis in ovarian cancer via NRF2-dependent and -independent pathways

Inhibition of palmitoyltransferase ZDHHC12 sensitizes ovarian cancer cells to cisplatin through ROS‐mediated mechanisms

AbstractPlatinum‐based therapies have revolutionized the treatment of high‐grade serous ovarian cancer (HGSOC). However, high rates of disease recurrence and progression remain a major clinical concern. Impaired mitochondrial function and dysregulated reactive oxygen species (ROS), hallmarks of cancer, hold potential as therapeutic targets for selectively sensitizing cisplatin treatment. Here, we uncover an oncogenic role of the palmitoyltransferase ZDHHC12 in regulating mitochondrial function and ROS homeostasis in HGSOC cells. Analysis of The Cancer Genome Atlas (TCGA) ovarian cancer data revealed significantly elevated ZDHHC12 expression, demonstrating the strongest positive association with ROS pathways among all ZDHHC enzymes. Transcriptomic analysis of independent ovarian cancer datasets and the SNU119 cell model corroborated this association, highlighting a strong link between ZDHHC12 expression and signature pathways involving mitochondrial oxidative metabolism and ROS regulation. Knockdown of ZDHHC12 disrupted this association, leading to increased cellular complexity, ATP levels, mitochondrial activity, and both mitochondrial and cellular ROS. This dysregulation, achieved by the siRNA knockdown of ZDHHC12 or treatment with the general palmitoylation inhibitor 2BP or the fatty acid synthase inhibitor C75, significantly enhanced cisplatin cytotoxicity in 2D and 3D spheroid models of HGSOC through ROS‐mediated mechanisms. Markedly, ZDHHC12 inhibition significantly augmented the anti‐tumor activity of cisplatin in an ovarian cancer xenograft tumor model, as well as in an ascites‐derived organoid line of platinum‐resistant ovarian cancer. Our data suggest the potential of ZDHHC12 as a promising target to improve the outcome of HGSOCs in response to platinum‐based chemotherapy.

The SGK3-Catalase antioxidant signaling axis drives cervical cancer growth and therapy resistance

Cancer cells frequently exhibit aberrant redox homeostasis and adaptation to oxidative stress. Hence abrogation of redox adaptation in cancer cells can be exploited for therapeutic benefit. Here we report SGK3 functions as an anti-oxidative factor to promote cell growth and drug resistance in cervical cancers harboring PIK3CA helical domain mutations. Mechanistically, SGK3 is activated upon oxidative stress and exerts anti-ROS activity by stabilizing and activating the antioxidant enzyme catalase. SGK3 interacts with and phosphorylates catalase, promoting its tetrameric state and activity. Meanwhile, SGK3 phosphorylates GSK3β and protects catalase from GSK3β-β-TrCP mediated ubiquitination and proteasomal degradation. Furthermore, SGK3 inhibition not only potentiates CDK4/6 inhibitor Palbociclib-mediated cytotoxicity, but also overcomes cisplatin resistance through ROS-mediated mechanisms. These data uncover the role of SGK3 in maintaining redox homeostasis and suggest that the SGK3-catalase antioxidant signaling axis may be therapeutically targeted to improve treatment efficacy for cervical cancers carrying PIK3CA helical domain mutations.