Nuclear FOXO proteins act as tumor suppressors by transcriptionally activating genes involved in apoptosis and cell cycle arrest, and these anticancer functions are inhibited by AKT‐induced phosphorylation and cytoplasmic sequestration of FOXOs. We found that, after AKT‐mediated phosphorylation at serine 319, FOXO1 binds to IQGAP1, a hub for activation of the MAPK pathway, and impedes IQGAP1‐dependent phosphorylation of ERK1/2 (pERK1/2). Conversely, decreased FOXO1 expression increases pERK1/2 in cancer cell lines and correlates with increased pERK1/2 levels in patient specimens and disease progression. Treatment of cancer cells with PI3K inhibitors or taxane causes FOXO1 localization in the nucleus, increased expression of pERK1/2, and drug resistance. These effects are reversed by administering a small FOXO1‐derived phospho‐mimicking peptide inhibitor in vitro and in mice. Our results show a tumor suppressor role of AKT‐phosphorylated FOXO1 in the cytoplasm and suggest that this function of FOXO1 can be harnessed to overcome chemoresistance in cancer. Synopsis AKT‐phosphorylated FOXO1 possesses a tumor suppressor function in the cytoplasm by binding to the scaffold protein IQGAP1, thereby inhibiting MAPK signaling. This role of FOXO1 can be exploited to overcome resistance to chemotherapies. AKT‐phosphorylated FOXO1 binds to IQGAP1—a hub for MAPK signaling—and impedes IQGAP1‐dependent phosphorylation of ERK1/2 (pERK1/2). Decreased FOXO1 expression induces an increase in pERK1/2 in cancer cell lines and correlates with increased pERK1/2 levels in patient specimens and with disease progression. Treatment of cancer cells with PI3K inhibitors or taxane causes FOXO1 localization in the nucleus, increased expression of pERK1/2, and drug resistance. Co‐treatment of cancer cells with a small FOXO1‐derived phospho‐mimicking peptide inhibitor overcomes chemoresistance in vitro and in mice.

Rationale: Enhancer RNA (eRNA) bi-directionally expresses from enhancer region and sense eRNA regulates adjacent mRNA in cis and in trans. However, it has remained unclear whether antisense eRNAs in different direction are functional or merely a reflection of enhancer activation.

Key Clinical Message: Gastric diverticulum in the posterior wall of the stomach is very rare, and it is easy to be misdiagnosed as a left adrenal mass on imaging. Therefore, we must consider the possibility of gastric diverticulum when diagnosing a left adrenal mass. This paper reports a case of gastric diverticulum that was misdiagnosed as a left adrenal mass on abdominal enhanced CT. The patient underwent laparoscopic adrenalectomy, but there was no mass in the left adrenal found during surgery. After the incision of the retroperitoneum, a cystic mass was found adjacent to the posterior gastric wall which turned out to be gastric diverticulum. This case suggests that gastric diverticulum, a rare disease, may be interpreted as an adrenal mass on imaging. Therefore, as a urologist, the gastric diverticulum must be excluded when CT suggests a mass in the left adrenal region.

Prostate cancer (PCa) is the most prevalent malignancy among men worldwide. Advanced prostate cancer is characterized by aggressive progression, limited therapeutic response, and poor prognosis. Elucidating its oncogenic mechanisms may provide new opportunities for targeted intervention. Increasing evidence suggests that modulating cytoprotective autophagy represents a promising strategy for improving cancer treatment efficacy and overcoming drug resistance. Here, we identified the G protein subunit GNG4 as a crucial regulator of prostate cancer development. GNG4 expression was markedly elevated in advanced prostate cancer phenotypes and positively correlated with tumor survival, apoptosis, and migration. Further analysis demonstrated that GNG4 depletion suppressed autophagy and enhanced cellular sensitivity to enzalutamide. Mechanistically, GNG4 interacts with GNB1 to stabilize the downstream effector protein GNAI3 through the ubiquitination-proteasome pathway. These three distinct G protein subunits form a functional complex that regulates intracellular autophagy and subsequently influences the malignant behavior of prostate cancer. Furthermore, inhibition of autophagy or GNG4 knockdown significantly increased the antitumor efficacy of enzalutamide both in vitro and in vivo. Our findings identified GNG4 as a pivotal modulator of prostate cancer progression and proposed it as a promising therapeutic target to enhance the clinical response to enzalutamide.