ABSTRACT
The EGFR-RAS-ERK pathway plays a key role in cancer development and progression. However, the integral assembly of EGFR-RAS-ERK signaling complexes from the upstream component EGFR to the downstream component ERK is largely unknown. Here, we show that hematopoietic PBX-interacting protein (HPIP) interacts with all classical components of the EGFR-RAS-ERK pathway and forms at least two complexes with overlapping components. Experiments of HPIP knockout or knockdown and chemical inhibition of HPIP expression showed that HPIP is required for EGFR-RAS-ERK signaling complex formation, EGFR-RAS-ERK signaling activation, and EGFR-RAS-ERK signaling-mediated promotion of aerobic glycolysis as well as cancer cell growth in vitro and in vivo. HPIP expression is correlated with EGFR-RAS-ERK signaling activation and predicts worse clinical outcomes in patients with lung cancer. These results provide insights into EGFR-RAS-ERK signaling complex formation and EGFR-RAS-ERK signaling regulation and suggest that HPIP may be a promising therapeutic target for cancer with dysregulated EGFR-RAS-ERK signaling.
Subject(s)
MAP Kinase Signaling System , Transcription Factors , Humans , Transcription Factors/metabolism , Cell Transformation, Neoplastic/genetics , ErbB Receptors/geneticsABSTRACT
CD8+ T lymphocyte-mediated immunity strategies have represented attractive weapons against breast cancer (BC) recently. However, the mechanisms underlying CD8+ T-lymphocyte infiltration still remain obscure. Here, using bioinformatics analysis, we identified four hub prognostic genes related to CD8+ T-lymphocyte infiltration (CHMP4A, CXCL9, GRHL2, and RPS29), among which CHMP4A was the most significant gene. High CHMP4A mRNA expression was significantly associated with longer overall survival (OS) in BC patients. Functional experiments showed that CHMP4A had the ability to promote CD8+ T-lymphocyte recruitment and infiltration and suppressed BC growth in vitro and in vivo. Mechanistically, CHMP4A stimulates CD8+ T-lymphocyte infiltration by downregulating LSD1 expression, leading to HERV dsRNA accumulation, and promoting IFNß and its downstream chemokine production. Collectively, CHMP4A is not only a novel positive predictor for prognosis in BC but also a stimulator of CD8+ T-lymphocyte infiltration regulated by the LSD1/IFNß pathway. This study suggests that CHMP4A may be a novel target for improving the effectiveness of immunotherapy in patients with BC.
Subject(s)
Breast Neoplasms , Mammary Neoplasms, Animal , Animals , Humans , Female , CD8-Positive T-Lymphocytes , Breast Neoplasms/metabolism , Prognosis , Mammary Neoplasms, Animal/metabolism , Histone Demethylases/genetics , Histone Demethylases/metabolism , Endosomal Sorting Complexes Required for Transport/metabolismABSTRACT
Aerobic glycolysis (Warburg effect), a hallmark of cancer, plays a critical role in cancer cell growth and metastasis; however, direct inhibition of the Warburg effect remains largely unknown. Herein, the transcription factor OVO-like zinc finger 2 (OVOL2) is demonstrated to directly repress the expression of several glycolytic genes, blocking the Warburg effect and breast tumor growth and metastasis in vitro and in vivo. OVOL2 inhibits glycolysis by recruiting the nuclear receptor co-repressor (NCoR) and histone deacetylase 3 (HDAC3). The tumor suppressor p53, a key regulator of cancer metabolism, activates OVOL2 by binding to the oncoprotein mouse double minute 2 homolog (MDM2) and inhibiting MDM2-mediated ubiquitination and degradation of OVOL2. OVOL2 expression is negatively correlated with glycolytic gene expression and can be a good predictor of prognosis in patients with breast cancer. Therefore, targeting the p53/MDM2/OVOL2 axis provides a potential avenue for cancer treatment, especially breast cancer.
Subject(s)
Neoplasms , Tumor Suppressor Protein p53 , Animals , Cell Line, Tumor , Co-Repressor Proteins/genetics , Co-Repressor Proteins/metabolism , Gene Expression , Glycolysis/genetics , Mice , Transcription Factors/genetics , Transcription Factors/metabolism , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Protein p53/metabolismABSTRACT
Lung adenocarcinoma (LUAD) is a common type of lung cancer with high frequent metastasis and a high death rate. However, genes responsible for LUAD metastasis are still largely unknown. Here, we identify an important role of ras homolog family member V (RHOV) in LUAD metastasis using a combination of bioinformatic analysis and functional experiments. Bioinformatic analysis shows five hub LUAD metastasis driver genes (RHOV, ZIC5, CYP4B1, GPR18 and TCP10L2), among which RHOV is the most significant gene associated with LUAD metastasis. High RHOV expression predicted shorter overall survival in LUAD patients. RHOV overexpression promotes proliferation, migration, and invasion of LUAD cells, whereas RHOV knockdown inhibits these biological behaviors. Moreover, knockdown of RHOV suppresses LUAD tumor growth and metastasis in nude mice. Mechanistically, RHOV activates Jun N-terminal Kinase (JNK)/c-Jun signalling pathway, an important pathway in lung cancer development and progression, and regulates the expression of markers of epithelial-to-mesenchymal transition, a process involved in cancer cell migration, invasion and metastasis. RHOV-induced malignant biological behaviors are inhibited by pyrazolanthrone, a JNK inhibitor. Our findings indicate a critical role of RHOV in LUAD metastasis and may provide a biomarker for prognostic prediction and a target for LUAD therapy.
Subject(s)
Adenocarcinoma of Lung/genetics , Cell Proliferation/genetics , Epithelial-Mesenchymal Transition/genetics , GTP-Binding Proteins/genetics , Lung Neoplasms/genetics , MAP Kinase Signaling System , Neoplasm Proteins/genetics , Adenocarcinoma of Lung/mortality , Adenocarcinoma of Lung/pathology , Animals , Cell Line, Tumor , Cell Movement/genetics , Gene Expression Regulation, Neoplastic , Humans , Lung Neoplasms/mortality , Lung Neoplasms/pathology , Mice , Mice, Nude , Neoplasm Metastasis , Prognosis , ROC Curve , Survival RateABSTRACT
[This corrects the article DOI: 10.3389/fcell.2020.615154.].
