Inhibition of LSD1 Attenuates Oral Cancer Development and Promotes Therapeutic Efficacy of Immune Checkpoint Blockade and YAP/TAZ Inhibition

Abstract

Lysine-specific demethylase 1 (LSD1) is a histone demethylase that contributes to the etiology of oral squamous cell carcinoma (OSCC) in part by promoting cancer stem cell phenotypes. The molecular signals regulated by LSD1, or acting with LSD1, are poorly understood, particularly in the development of OSSC. In this study, we show that conditional deletion of the Lsd1 gene or pharmacologic inhibition of LSD1 in the tongue epithelium leads to reduced development of OSCC following exposure to the tobacco carcinogen 4NQO. LSD1 inhibition attenuated proliferation and clonogenic survival and showed an additive effect when combined with the YAP inhibitor Verteporfin. Interestingly, LSD1 inhibition upregulated the expression of PD-L1, leading to immune checkpoint inhibitor therapy responses. Implications: Collectively, our studies reveal a critical role for LSD1 in OSCC development and identification of tumor growth targeting strategies that can be combined with LSD1 inhibition for improved therapeutic application.

Targeting the YAP/TAZ mechanotransducers in solid tumour therapeutics

“…YAP/TAZ mediates resistance to progestin through the phosphoinositide 3‐kinase (PI3K)/Akt pathway, and VP sensitizes EC cells to progestin both in vitro and in vivo 23 . It also demonstrates an additive antitumor effect when combined with the histone demethylase lysine‐specific demethylase 1 (LSD1) inhibitor SP2509 in vitro and in vivo in oral squamous cell carcinoma cells 24 …”

“…23 It also demonstrates an additive antitumor effect when combined with the histone demethylase lysine-specific demethylase 1 (LSD1) inhibitor SP2509 in vitro and in vivo in oral squamous cell carcinoma cells. 24 There are also selective inhibitors of TEAD. K-975 is a newly identified highly selective TEAD inhibitor that impairs YAP/TAZ-TEAD protein-protein interactions.…”

Mechanisms of carcinogenic activity triggered by lysine-specific demethylase 1A

“…Inhibition of LSD1 increases the expression of effector T cell-attracting chemokine factors and PD-L1 and promotes the trafficking of CD8 + T lymphocytes in the microenvironment of TNBC ( Qin et al, 2019 ). Knockout of LSD1 or inhibition of LSD1 activity can also enhance the immune response of T cells in various cancers, such as cervical, ovarian, gastric, and oral cancers ( Soldi et al, 2020 ; Xu et al, 2021 ; Alhousami et al, 2022 ; Shen et al, 2022 ). Therefore, LSD1 inhibition may be an effective adjuvant for immunotherapy in patients with poorly immunogenic cancers.…”

Integrating Genetic Alterations and the Hippo Pathway in Head and Neck Squamous Cell Carcinoma for Future Precision Medicine

“…Cyclin dependent kinase 7 (CDK7) phosphorylates YAP/TAZ at S128 and S90 to avoid ubiquitination for degradation by the CRL4 DCAF12 E3 ubiquitin ligase complex [ 109 ]. Lysine-specific demethylase 1 (LSD1), a histone demethylase encoded by KDM1A gene, forms the nucleosome remodeling and deacetylase complex with YAP, enhancing the transcription of YAP-target genes [ 110 ]. Moreover, YAP/TAZ promotes polyamine levels and cell proliferation by activating transcription of ornithine decarboxylase 1 (Odc1), inducing the hypusination of eukaryotic translation factor 5A (eIF5A) to enhance translation of LSD1 [ 111 ].…”

“…Five drugs including BI-894999, BPI-23314, NUV-868, PLX-2853, and SYHA-1801 are in Phase I or II clinical trials ( Table 1 ). LSD1 knockout reportedly suppressed 4NQO-driven mouse tongue oral squamous cell carcinoma and LSD1 inhibition by SP2509 inhibited 4NQO-driven oral squamous cell carcinoma in combination with verteporfin [ 110 ]. Inhibition of LSD1 by SP-2577 inhibited liver carcinogenesis in YAP transgenic mice and breast cancer cell growth in an in vivo xenograft model [ 111 ] ( Figure 5 ).…”