Loss of LOXL2 Promotes Uterine Hypertrophy and Tumor Progression by Enhancing H3K36ac-Dependent Gene Expression

Abstract

Lysyl oxidase-like 2 (LOXL2) is a member of the scavenger-receptor cysteine-rich (SRCR) repeat carrying LOX family. Although LOXL2 is suspected to be involved in histone association and chromatin modification, the role of LOXL2 in epigenetic regulation during tumorigenesis and cancer progression remains unclear. Here, we report that nuclear LOXL2 associates with histone H3 and catalyzes H3K36ac deacetylation and deacetylimination. Both the N-terminal SRCR repeats and the C-terminal catalytic domain of LOXL2 carry redundant deacetylase catalytic activity. Overexpression of LOXL2 markedly reduced H3K36 acetylation and blocked H3K36ac-dependent transcription of genes, including c-MYC, CCND1, HIF1A, and CD44. Consequently, LOXL2 overexpression reduced cancer cell proliferation in vitro and inhibited xenograft tumor growth in vivo. In contrast, LOXL2 deficiency resulted in increased H3K36 acetylation and aberrant expression of H3K36ac-dependent genes involved in multiple oncogenic signaling pathways. Female LOXL2 deficient mice spontaneously developed uterine hypertrophy and uterine carcinoma. Moreover, silencing LOXL2 in cancer cells enhanced tumor progression and reduced the efficacy of cisplatin and anti-programmed cell death 1 (PD-1) combination therapy. Clinically, low nuclear LOXL2 expression and high H3K36ac levels corresponded to poor prognosis in uterine endometrial carcinoma patients. These results suggest that nuclear LOXL2 restricts cancer development in the female reproductive system via regulation of H3K36ac deacetylation.

Prognostic value and immunological function of cuproptosis-related genes in lung adenocarcinoma

“…Lysyl oxidase-like 2 (LOXL2) is a member of the scavenger-receptor cysteine-rich (SRCR) family that carries LOX, which is related to histone binding and chromatin modification. Studies have demonstrated that LOXL2 is a tumor suppressor, and low expression of LOXL2 can promote the progress of uterine cancer and inhibit the efficacy of anti-PD-1 therapy [ 42 ]. Thus, CRGs may play an important role in the occurrence and development of several types of tumors, but with few studies in LUAD.…”

Prognostic value and immunological function of cuproptosis-related genes in lung adenocarcinoma

“…Lysyl oxidase-like 2 (LOXL2) is a member of the scavenger-receptor cysteine-rich (SRCR) family that carries LOX, which is related to histone binding and chromatin modi cation. Studies have demonstrated that LOXL2 is a tumor suppressor, and low expression of LOXL2 can promote the progress of uterine cancer and inhibit the e cacy of anti-PD-1 therapy 27 . Thus, CRGs may play an important role in the occurrence and development of several types of tumors, but with few studies in LUAD.…”

Elesclomol Loaded Copper Oxide Nanoplatform Triggers Cuproptosis to Enhance Antitumor Immunotherapy

“…Finally, the stained cells were analyzed via a flow cytometer (Beckman Coulter). [ 45 ] Data analysis was conducted using FlowJo software (BD, USA). The types of immune cells were subjected to density clustering after they were identified using nonlinear dimensionality reduction [t‐distributed stochastic neighbor embedding (t‐SNE)].…”

“…Finally, the sections were stained with 3,3′‐diaminobenzidine (DAB) for color development. [ 45 ] The slides were then counterstained with hematoxylin, dehydrated, and imaged under an optical microscope (Nikon, Japan).…”