Hippo effector YAP directly regulates the expression of PD-L1 transcripts in EGFR-TKI-resistant lung adenocarcinoma

Journal Article · Sat Sep 16 04:00:00 EDT 2017 · Biochemical and Biophysical Research Communications

DOI:https://doi.org/10.1016/J.BBRC.2017.07.007· OSTI ID:22719081

Lee, Byung Soo; Park, Dong Il; Lee, Da Hye; Lee, Jeong Eun ^[1]; Yeo, Min-kyung ^[2]; Park, Yeon Hee ^[1]; Lim, Dae Sik; Choi, Wonyoung; Lee, Da Hye; Yoo, Geon; Kim, Han-byul ^[3]; Kang, Dahyun; Moon, Jae Young; Jung, Sung Soo; Kim, Ju Ock ^[1]; Chung, Chaeuk ^[1]

---

1. Division of Pulmonology, Department of Internal Medicine, College of Medicine, Chungnam National University, Daejeon 35015 (Korea, Republic of)
2. Department of Pathology, College of Medicine, Chungnam National University, Daejeon 35015 (Korea, Republic of)
3. National Creative Research Center for Cell Division and Differentiation, Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141 (Korea, Republic of)

Developments of EGFR-TKI and immunotherapy targeting the PD1/PD-L1 pathway are considered most important medical breakthroughs in lung cancer treatment. Nowadays, 3rd generation EGFR TKI is widely used for T790M positive 1st and 2nd EGFR-TKI resistant lung cancer patients. Immunotherapy is powerful option for lung cancer patients without drug targets and chemotherapy resistant patients. It also has changed the concept of conventional anti-cancer therapy in the point of regulating tumor microenvironment. There are many studies linking these two important pathways. Recent studies demonstrated that PD-L1 expression is significantly correlated to the mutation status of EGFR, and activation of EGFR signaling can also induce the expression of PD-L1. However, the real linker between PD-L1 and EGFR signaling remains to be revealed. Our previous study revealed that the Hippo pathway effector YAP confers EGFR-TKI resistance in lung adenocarcinoma, and inhibition of YAP restores sensitivity to EGFR-TKIs. Thus, we examined whether PD-L1 is relevant, in terms of conferring EGFR-TKI resistance and whether YAP directly regulates the expression of PD-L1 in this context. First, we compared the expression levels of PD-L1 and YAP between EGFR-TKI-resistant PC9 cells and the parental PC9 adenocarcinoma cells. The expression levels of both YAP and PD-L1 were markedly higher in the EGFR-TKI-resistant cells compared to the parental cells, suggesting differential expression pattern between two cell types. YAP knockdown significantly decreased the expression of PD-L1 in the EGFR-TKI-resistant cells, while YAP overexpression increased the expression of PD-L1 in the parental PC9 cells. Then, our results revealed that YAP regulates the transcription of PD-L1, and the YAP/TEAD complex binds to the PD-L1 promoter. Surprisingly, knockdown of PD-L1 was sufficient to decrease cell proliferation and wound healing in the EGFR-TKI-resistant PC9 cells. These data suggest a PD1-independent oncogenic function of PD-L1. The Hippo effector YAP plays a crucial role in linking the PD-L1 and EGFR-TKI resistance by directly regulating the expression of PD-L1 in lung cancer. Targeting PD-L1 directly or via YAP could provide an effective therapeutic strategy for EGFR-TKI-resistant lung adenocarcinoma. - Highlights: • PD-L1 expression is elevated in EGFR-TKI-resistant PC9/GR cells compared to that of the parental PC9 cells. • YAP regulates PD-L1 at the transcript level in lung adenocarcinoma. • YAP/PD-L1 signaling regulates cell proliferation and migration independently of T cells and PD1. • The expressions of PD-L1 and YAP are positively correlated in lung adenocarcinoma.

• OSTI ID: 22719081
• Journal Information: Biochemical and Biophysical Research Communications, Journal Name: Biochemical and Biophysical Research Communications Journal Issue: 2 Vol. 491; ISSN BBRCA9; ISSN 0006-291X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
CARCINOMAS
CELL PROLIFERATION
CHEMOTHERAPY
HEALING
IMMUNOTHERAPY
LUNGS
PATIENTS
SIGNALS
WOUNDS