HP1{gamma} promotes lung adenocarcinoma by downregulating the transcription-repressive regulators NCOR2 and ZBTB7A

Lung adenocarcinoma (LUAD) is a major form of lung cancer, which is the leading cause of cancer death. Histone methylation reader proteins mediate the effect of histone methylation, a hallmark of epigenetic and transcriptional regulation of gene expression. However, their roles in LUAD are poorly understood. Here our bioinformatic screening and analysis in search of an LUAD-promoting histone methylation reader protein show that heterochromatin protein 1γ (HP1γ; also called CBX3) is among the most frequently overexpressed and amplified histone reader proteins in human LUAD, and that high HP1γ mRNA levels are associated with poor prognosis in LUAD patients. In vivo depletion of HP1γ reduced K-RasG12D-driven LUAD and lengthened survival of mice bearing K-RasG12D-induced LUAD. HP1γ and its binding activity to methylated histone H3 lysine 9 were required for the proliferation, colony formation, and migration of LUAD cells. HP1γ directly repressed expression of the transcription-repressive regulators NCOR2 and ZBTB7A. Knockdown of NCOR2 or ZBTB7A significantly restored defects in proliferation, colony formation, and migration in HP1γ-depleted LUAD cells. Low NCOR2 or ZBTB7A mRNA levels were associated with poor prognosis in LUAD patients and correlated with high HP1γ mRNA levels in LUAD samples. NCOR2 and ZBTB7A downregulated expression of tumor-promoting factors such as ELK1 and AXL, respectively. These findings highlight the importance of HP1γ and its reader activity in LUAD tumorigenesis and reveal a unique LUAD-promoting mechanism in which HP1γ downregulates NCOR2 and ZBTB7A to enhance expression of pro-tumorigenic genes.

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