Selected Articles from This Issue

Bone metastasis is a common complication of advanced castration-resistant prostate cancer (CRPC), but there are no targeted treatments for bone metastasis. To address this, Kim and colleagues studied the transcriptional targets of pS473-TRIM28 and evaluated how the TRIM28/LDHA axis can be targeted to reduce bone metastasis in CRPC. RNA sequencing, DepMap-informed CRISPR-mediated knockout studies, CUT&RUN sequencing, and luciferase assays found a dependence on TRIM28 in prostate cancer cell lines and identified LDHA as a downstream target of TRIM28. Further analysis using Lactate-Glo assays and seahorse glycolytic assays showed a decrease in cellular and extracellular lactate levels and glycolytic activity upon TRIM28 knockdown, TRIM28-S473A expression, and LDHA knockdown compared to the control. IVIS analysis of C4-2B cells transduced with TRIM28 or LDHA knockdown constructs and injected into NSG mouse tibias found reduced bioluminescent signals in TRIM28 and LDHA knockdown tumors compared to the control. Rescue studies for TRIM28-S473 phosphorylation also exhibited reduced bioluminescent signals. The authors also treated bone metastatic prostate cancer models with LDH inhibitor, FX-11, finding a decrease in the colony formation ability in vitro and reduced bioluminescent signals in orthotopic bone injection models. Altogether, this study highlights the TRIM28/LDHA axis in CRPC and proposes it has a potential therapeutic target to reduce bone metastasis.Colorectal cancer is an aggressive malignancy with poor outcomes in late-stage patients. Despite this, our understanding of the molecular mechanism driving the progression of this disease is limited. In their study, Qi and colleagues analyzed a cohort of colorectal cancer transcriptomic datasets to determine the major contributors to colorectal cancer pathogenesis. Integrated transcriptomic analysis and LASSO analysis identified DBNDD1 as a key gene associated with colorectal cancer. Proliferation, apoptosis, and colony formation assays of DBNDD1 knockdown cells showed decreased proliferation and colony formation ability, but increased levels of apoptosis. Expression of mesenchymal markers and inflammatory markers were also reduced upon DBNDD1 knockdown. In vivo DBNDD1-deficient xenograft tumors had reduced volume and weight compared to the control, and the spleen capsule injection model and tail vein injection model using DBNDD1-deficient cells revealed a reduced number of metastases compared to the controls. Colocalization of DBNDD1 and GDF15 was observed using laser confocal microscopy, and coimmunoprecipitation demonstrated their direct interaction. Genetic manipulation of DBNDD1 and GDF15 in colorectal cancer cells further found that prometastatic markers were upregulated and the NF-κB signaling pathway was activated upon high expression of DBNDD1 and GDF15, indicating these molecules may have a tumor-promoting synergistic relationship.Cell death mechanisms in cancer are widely studied, but the molecular underpinning of chaperone-mediated autophagy (CMA) in HPV− head and neck squamous cell carcinoma (HNSCC) is unclear. To elucidate CMA substrates in HNSCC, Cao and colleagues perform integrated proteomics and motif analysis to find targets of rate-limiting protein LAMP2A. IP–LC/MS-MS analysis of HNSCC cells, followed by proteomics, identified SELENBP1 as an LAMP2A-interacting protein. Coimmunoprecipitation further validated direct interaction between SELENBP1 and LAMP2A. LAMP2A knockdown inhibited CMA and showed increased expression of SELENBP1. Additionally, overexpression of SELENBP1 decreased HNSCC cell proliferation and increased apoptosis, while CCK-8 assays, EdU assays, and flow cytometry analysis of LAMP2A knockdown cells demonstrated decreased cell viability and proliferation. Expression of cancer stem cell markers, the CD133+ cancer stem cell population, and tumor sphere formation ability were also decreased upon LAMP2A knockdown. The authors found that concurrent knockdown of SELENBP1 and LAMP2A rescued the apoptotic rate of HNSCC cells. Overall, this study highlights the role of CMA in HNSCC progression and identifies the LAMP2A–CMA–SELENBP1 axis.