Enomoto, K. | bioRxiv Science

bioRxiv2025

HIF2-driven PTHrP Causes Cachexia and Hypercalcemia in Kidney Cancer: Treatment with HIF2 Inhibitors

Kidney cancer frequently causes paraneoplastic syndromes, including hypercalcemia and cachexia, but the underlying mechanisms are incompletely understood. The most common form of kidney cancer, clear cell renal cell carcinoma, is frequently caused by loss of the pVHL tumor suppressor protein and the resulting upregulation of the HIF2 transcription factor. We show that PTHLH, which resides on a ccRCC amplicon on chromosome 12p, is a direct HIF2 transcriptional target in ccRCC. Further, we show that the increased PTHLH expression is both necessary and sufficient for the induction of hypercalcemia and cachexia in preclinical orthotopic cell line tumor models. Consistent with these observations, two different allosteric HIF2 inhibitors, belzutifan and NKT2152, rapidly ameliorated hypercalcemia and cachexia in ccRCC patients, including in some patients who did not exhibit objective tumor shrinkage.

cancer biology↗

bioRxiv2024

Diurnal regulation of SOS Pathway and Sodium Excretion Underlying Salinity Tolerance of Vigna marina

Vigna marina (Barm.) Merr. is adapted to tropical marine beaches and has an outstanding tolerance to salt stress. Given there are growing demands for cultivating crops in saline soil or with saline water, it is important to understand how halophytic species are adapted to the saline environments. Here we revealed by positron emitting tracer imaging system (PETIS) that V. marina actively excretes sodium from the root during the light period but not in the dark period. The following whole genome sequencing accompanied with forward genetic study identified a QTL region harboring SOS1, encoding plasma membrane Na+/H+ antiporter, which was associated with not only salt tolerance but also ability of sodium excretion. We also found the QTL region contained a large structural rearrangement that suppressed recombination across [~]20 Mbp, fixing multiple gene loci potentially involved in salt tolerance. RNA-seq and promoter analyses revealed SOS1 in V. marina was highly expressed even without salt stress and its promoter shared common cis-regulatory motifs with those exhibiting similar expression profile. Interestingly, the cis-regulatory motifs seemed installed by a transposable element (TE) insertion. Though not identified by genetic analysis, the transcriptome data also revealed SOS2 transcription was under diurnal regulation, explaining the pattern of sodium excretion together with up-regulated expression of SOS1. Furthermore, we demonstrated that, under a condition of mild salt stress, the plants with the diurnally regulated SOS pathway outperformed those with the constitutively activated one.

plant biology↗