Faculty Bibliography

Lung cancer remains a leading cause for global cancer-related mortality, with therapeutic resistance and metastasis posing major clinical challenges. The special AT-rich sequence-binding protein 2 (SATB2) is a well-established tumor suppressor in NSCLC, but its downstream epigenetic and metabolic regulatory mechanisms remain largely unclear. Here, we demonstrate that SATB2 exerts tumor-suppressive effects by impairing NSCLC cell proliferation, migration, invasion, and EMT. Mechanistically, SATB2 functions as a negative regulator of global histone lactylation, with a specific role in reducing histone H3 lysine 9 lactylation (H3K9la)-a previously uncharacterized histone mark in NSCLC. Through integrated multi-omics analyses (RNA-seq and H3K9la-specific CUT&Tag), we identified Lipocalin-2 (LCN2), an oncoprotein, as a critical downstream target of the SATB2-H3K9la axis. SATB2 is able to bind LCN2 promoter and recruit histone deacetylase 3 (HDAC3) via its N-terminal domain, catalyzing H3K9 delactylation to repress LCN2 transcription. Exogenous lactate reversed SATB2-mediated H3K9la and LCN2 suppression, restoring oncogenic phenotypes. In vivo, SATB2 overexpression inhibited xenograft tumor growth and lung metastasis, while LCN2 overexpression rescued these suppressive effects. Our findings uncover a novel epigenetic-metabolic crosstalk pathway in NSCLC, providing new insights into the molecular mechanisms of SATB2-mediated tumor suppression and potential therapeutic targets for NSCLC.

Both visual and vestibular sensory cues are important for perceiving one's direction of heading during self-motion. Previous studies have identified multisensory, heading-selective neurons in the dorsal medial superior temporal area (MSTd) and the ventral intraparietal area (VIP). Both MSTd and VIP have strong recurrent connections with the pursuit area of the frontal eye field (FEFsem), but whether FEFsem neurons may contribute to multisensory heading perception remain unknown. We characterized the tuning of macaque FEFsem neurons to visual, vestibular, and multisensory heading stimuli. About two-thirds of FEFsem neurons exhibited significant heading selectivity based on either vestibular or visual stimulation. These multisensory neurons shared many properties, including distributions of tuning strength and heading preferences, with MSTd and VIP neurons. Fisher information analysis also revealed that the average FEFsem neuron was almost as sensitive as MSTd or VIP cells. Visual and vestibular heading preferences in FEFsem tended to be either matched (congruent cells) or discrepant (opposite cells), such that combined stimulation strengthened heading selectivity for congruent cells but weakened heading selectivity for opposite cells. These findings demonstrate that, in addition to oculomotor functions, FEFsem neurons also exhibit properties that may allow them to contribute to a cortical network that processes multisensory heading cues.