Selected Articles from This Issue

Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is caused by loss of function mutations in fumarate hydratase (FH) and results in an aggressive subtype of renal cell carcinoma with limited treatment options. FH loss results in accumulation of fumarate, an oncometabolite that inhibits alpha ketoglutarate-dependent dioxygenases and leads to global DNA hypermethylation. Noronha and colleagues found that hypermethylation in FH-deficient samples is associated with silencing of nicotinate phosphoribosyl transferase (NAPRT), which encodes a rate-limiting enzyme in NAD+ biosynthesis. FH-deficient RCC models with loss of NAPRT expression, and other oncometabolite-producing cancers with NAPRT loss, were highly sensitive to nicotinamide phosphoribosyl transferase inhibitors (NAMPTis). Furthermore, synergistic cytotoxicity with combined inhibition of poly (ADP-ribose) PARP and NAMPT was observed in cells with NAPRT expression loss, likely due to increased impairment of PAR-mediated DNA repair from NAD+ depletion. In sum, this study uncovers how oncometabolite-associated hypermethylation can lead to therapeutically actionable vulnerabilities in cancer and presents NAPRT as a novel biomarker for targeting NAD+ metabolism and DNA repair processes in FH-deficient HLRCCs and other oncometabolite-producing tumors.Glycolytic metabolic reprogramming contributes to tumorigenesis, and elevated plasma lactate (LA) serves as a crucial regulator in the progression of various human malignancies. To elucidate the potential molecular mechanisms of cancer progression in response to LA, Du and colleagues conducted in vitro and in vivo experiments using various cancer cell types and a murine xenograft model. Their findings indicated that reduction of Yin-Yang 1 (YY1) abundance, which correlates with high LA levels, is common in various cancer cell types, including B cell lymphoma and cervical cancer. Mechanistically, LA triggers the nuclear export and subsequent degradation of YY1 via HSP70-mediated autophagy that occurs in proximity to mitochondria, facilitated by YY1’s histidine-rich lactate-responsive (LAR) motif. Mutation of the LAR motif prevents LA-induced cytoplasmic accumulation of YY1, thereby enhancing cellular apoptosis. Moreover, reduced YY1 abundance facilitates colony formation, invasion, angiogenesis, and the growth of cancer cells in response to LA. Collectively, this study identifies a crucial YY1 LAR element that may serve as a therapeutic target for intervening in cancer progression.Wnt signaling pathway (WSP) alterations have been identified in prostate cancer patients and are implicated in disease progression and hormonal resistance. Choi and colleagues used a multi-institutional real-world dataset of comprehensive tumor molecular profiles integrated with clinical data from prostate cancer patients to characterize molecular alterations in canonical and noncanonical WSP. The authors found that WSP-activated tumors, characterized by activating mutations in CTNNB1 or RSPO2, or inactivating mutations in APC or RNF43, were more prevalent in metastatic sites than in primary prostate tumors. WSP-activated prostate cancer exhibited more SPOP mutations and lower androgen receptor signaling gene signature scores than WSP wild-type tumors. Transcriptomic analysis identified a pronounced upregulation of a non-canonical WSP coreceptor, ROR1, in WSP-activated tumors and immunosuppressive M2 macrophage enrichment in the tumor microenvironment. Taken together, this study presents a novel framework for WSP-activated prostate cancer, demonstrates evidence of crosstalk between canonical and noncanonical Wnt signaling pathways, and provides a rationale for developing novel therapeutic strategies targeting Wnt-activated prostate cancer.The blast crisis (BC) phase of chronic myeloid leukemia (CML) exhibits low overall survival rates. To explore RNA binding protein contributions to the CML-BC transition, Zhou and colleagues assessed RNA binding protein-encoding transcript expression levels in CML-BC using public data and discovered elevated Lin28B expression. shRNA-mediated Lin28B ablation decreased clonogenicity and proliferation in CML cell lines, confirming a role for Lin28B in CML. Sequence analysis revealed Lin28B motifs in the promoter regulating expression of miR-181d, a miRNA previously shown to mediate the CML-BC transition. Chromatin immunoprecipitation experiments identified Lin28B binding at the miR-181d promoter, and Lin28B silencing decreased miR-181d expression. Bioinformatic analysis nominated programmed cell death 4 (PDCD4) as a miR-181d target, which was functionally verified using miR-181d mimics and inhibitors. siRNA-mediated PDCD4 abrogation restored clone formation and proliferation in Lin28B-deficient CML cells, confirming Lin28B facilitates CML malignancy via PDCD4 suppression. Lin28B shRNA-expressing CML cells also demonstrated reduced tumor growth in a mouse model. Overall, this study presents a DNA binding function of Lin28B, and identifies a novel miR-181d/PDCD4 axis through which it promotes CML-BC malignancy.