HP1γ Promotes Lung Adenocarcinoma by Downregulating the Transcription-Repressive Regulators NCOR2 and ZBTB7A

Abstract

Lung adenocarcinoma 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 lung adenocarcinoma are poorly understood. Here, our bioinformatic screening and analysis in search of a lung adenocarcinoma-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 lung adenocarcinoma, and that high <i>HP1γ</i> mRNA levels are associated with poor prognosis in patients with lung adenocarcinoma. <i>In vivo</i> depletion of HP1γ reduced K-Ras^G12D-driven lung adenocarcinoma and lengthened survival of mice bearing K-Ras^G12D-induced lung adenocarcinoma. HP1γ and its binding activity to methylated histone H3 lysine 9 were required for the proliferation, colony formation, and migration of lung adenocarcinoma 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 lung adenocarcinoma cells. Low <i>NCOR2</i> or <i>ZBTB7A</i> mRNA levels were associated with poor prognosis in patients with lung adenocarcinoma and correlated with high <i>HP1γ</i> mRNA levels in lung adenocarcinoma 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 lung adenocarcinoma tumorigenesis and reveal a unique lung adenocarcinoma-promoting mechanism in which HP1γ downregulates NCOR2 and ZBTB7A to enhance expression of protumorigenic genes.<b>Significance:</b> Direct epigenetic repression of the transcription-repressive regulators NCOR2 and ZBTB7A by the histone reader protein HP1γ leads to activation of protumorigenic genes in lung adenocarcinoma. <i>Cancer Res; 78(14); 3834-48. ©2018 AACR</i>.