LSD1 modulates the bone metastasis of breast cancer cells through hnRNPA2B1-mediated sorting of exosomal miRNAs.

Bone metastasis is a key contributor to morbidity and mortality of breast cancer patients. We have previously shown that exosomal miRNAs derived from LSD1 knockdown (KD) breast cancer cells inhibit osteoblast differentiation and promote osteoclast differentiation. However, how LSD1 regulates exosomal miRNAs and whether miRNAs promote bone metastasis through the formation of pre-metastatic niches remains unclear. In vivo experiments demonstrates that exosomes derived from LSD1 KD breast cancer cells significantly promoted bone metastasis. To explore the mechanism underlying the effect of LSD1 on exosomes in breast cancer cells, exosomal and cellular miRNAs from control, LSD1 KD, and rescue cells were sequenced. Interestingly, approximately 80% of LSD1-associated miRNAs were downregulated in exosomes from LSD1 KD cells. The consensus sequence UAGGGC, was identified in many miRNAs downregulated in LSD1 KD exosomes. We found that hnRNPA2B1 regulated the exosomal sorting of miR-6881-3p and some other miRNAs. LSD1 deficiency reduced hnRNPA2B1 expression in breast cancer cells by decreasing the level of H3K9me2 demethylation in the promoter region of the hnRNPA2B1 gene. Our study revealed that LSD1 plays a crucial role in the regulation of exosomal sorting of miRNA.

Exosomes from LSD1 knockdown breast cancer cells activate osteoclastogenesis and inhibit osteoblastogenesis.

Bone metastasis is a common and incurable complication of breast cancer. Lysine-specific demethylase 1 (LSD1), a histone demethylase, plays an important role in the metastasis of breast cancer. However, the role of LSD1 in bone metastasis of breast cancer is unclear. We hypothesized that exosomes from LSD1 knockdown breast cancer cells promote bone metastasis by remodeling bone microenvironment. To verify this hypothesis, exosomes from LSD1 knockdown Estrogen receptor-positive cancer cell lines, MCF7 and T47D, were isolated, and the effects of these exosomes on osteoblast and osteoclast differentiation were investigated. Interestingly, exosomes from LSD1 knockdown breast cancer cells inhibited osteoblast differentiation and promoted osteoclast differentiation. Mechanistically, miR-6881-3p was decreased in the exosomes from LSD1 knockdown cells, and miR-6881-3p suppressed the expression of pre-B-cell leukemia homeobox 1 (PBX1) and additional sex combs like-2 (ASXL2), two genes with essential functions in osteoblast and osteoclast differentiations respectively. Transfection of miR-6881-3p into LSD1 knockdown cells reversed the effects of the exosomes on osteoblast and osteoclast differentiations. Our study reveals important roles of LSD1 on the regulation of exosomal miRNAs and the formation of favorable bone microenvironment for metastasis.

Development of an antibacterial surface with a self-defensive and pH-responsive function.

In this work, a charge conversion mechanism was introduced to build a bacteria responsive antibacterial surface. The antimicrobial surface is constructed by immobilizing pH-responsive moieties on the surface of the material, followed by immobilization of the antimicrobial peptide (AMP) melittin (MLT) by strong electrostatic interaction. The constructed surface exhibited self-defensive properties against Gram-positive and Gram-negative bacteria. In comparison with previously reported self-defensive systems with side effects of drug resistance, this antibacterial surface prevented the undesirable drug resistance. The bactericidal mechanism of the antibacterial surface is involved in a lytic cell membrane. Once bacteria come into contact with the surface, the bactericidal properties will be triggered on the surface. As bacteria exponentially grow, they accumulate and attach to the surface, which will develop a slightly acidic micro-environment and subsequently activate the pH responsive surface to release MLT to kill bacteria. This study broadened our understanding of the development of antibacterial surfaces and provided new insights for the antibacterial surface to be utilized in industrial, biological and medical applications.