MIR210HG promotes breast cancer progression by IGF2BP1 mediated m6A modification.

BACKGROUND: Breast cancer is the most common cancer in women around the world, and the molecular mechanisms of breast cancer progression and metastasis are still unclear. This study aims to clarify the function and N6,2'-O-dimethyladenosine (m6A) regulation of lncRNA MIR210HG in breast cancer. RESULTS: High expression of MIR210HG was confirmed in breast cancer. MIR210HG promoted breast cancer progression, which was mediated by its encoded miR-210. MIR210HG was regulated by IGF2BP1 mediated m6A modification. IGF2BP1 was confirmed highly expressed in breast cancer and induced both MIR210HG and miR-210 expression, which contributed to breast cancer progression. In addition, MIR210HG transcript was stabilized by IGF2BP1 and co-factor ELAVL1. IGF2BP1 was a direct target of MYCN via E-box binding motif. MYCN induced IGF2BP1 expression in breast cancer cells. MIR210HG and miR-210 expressions were also increased by MYCN. CONCLUSIONS: In breast cancer, MIR210HG functions as an oncogenic lncRNA, which is also mediated by its encoded miR-210. In addition, both IGF2BP1 and ELAVL1 enhance the stability of MIR210HG, which contributes to the progression of breast cancer. Interestingly, IGF2BP1 is directly activated by MYCN, which explains the oncogenic role of MYCN. These findings clarify the m6A regulation related molecular mechanism of breast cancer progression. The MYCN/IGF2BP1/MIR210HG axis may serve as an alternative molecular mechanism of breast cancer progression.

A gain-of-function mutation in PDR1 of Candida glabrata decreases EPA1 expression and attenuates adherence to epithelial cells through enhancing recruitment of the Mediator subunit Gal11A.

Genetic studies have revealed critical roles of transcription factor Pdr1 and the Mediator subunit Gal11A in regulating azole resistance in Candida glabrata. Recently, PDR1 gain-of-function (GOF) mutations have been shown to not only increase azole resistance but also enhance adherence during C. glabrata infection. However, mechanism of how Pdr1 regulates adherence, especially the implication of PDR1 GOF mutations in the regulation of the major adhesin gene EPA1, remains uncharacterized. Initially, we unexpectedly observed that expression of PDR1 harbouring GOF mutation G346D down-regulated EPA1 transcription and attenuated adherence to epithelial cells in different strain backgrounds. Given that PDR1 GOF mutations have been previously regarded as stimulators for adherence of this species, these findings prompted us to explore the regulation of EPA1 by wild-type Pdr1 and Pdr1 harbouring G346D mutation. Epitope tagged version of Pdr1 and Gal11A were utilized to determine the association of Pdr1 and Gal11A with EPA1 promoter. A combination of approaches including deletion, molecular, and biochemical assays showed that EPA1 is a direct target of Pdr1, and demonstrated for the first time that PDR1 G346D mutation decreases EPA1 expression and attenuates adherence to epithelial cells via enhancing recruitment of Gal11A. Taken together, our data propose a critical role of Gal11A in Pdr1-regulated EPA1 expression and adherence to epithelial cells, which could be utilized a novel therapeutic target for the treatment of hyper-adherent C. glabrata infection.