BIN2 Inhibition Suppress Cancer Progression and Protect Ovarian function through Downregulating HDAC1 and RPS6 Phosphorylation Respectively [CUT&Tag]
Malignant tumors, or cancers, are increasingly menacing people's life and health. For your female cancer patient, the ideal therapy should achieve dual purpose: suppress tumor progression meanwhile protect ovarian function. We previously showed that activated (phosphorylated) BIN2 in mouse ovaries regulates primordial follicle activation and oocyte quality through p-RPS6, and in this study, we found that BIN2 knockout or inhibition of BIN2 phosphorylation by BPP could suppress the genesis and progression of ovarian cancer. However, in human female ovarian cancer tissues, we didn't see the increment of p-RPS6 although we observed a significant raise of p-BIN2. From this discrepancy between normal ovaries and ovarian cancer tissue, we guessed that p-BIN2 has other targets that are more important in ovarian cancer progression. Through mass spec identification, we found that only the constitutively active form of BIN2 (T423D & S424D) baits HDAC1, indicating that HDAC1 is a more important target of BIN2 in ovarian cancer. Next, we did saw Bin2 knockout or inhibition significantly decreased p-HDAC1 (S421) meanwhile increased H3K27ac. Moreover, chip seq showed that BIN2 inhibition significantly increased the binding of H3K27ac to multiple oncogenes. Besides, BIN2 knockout or inhibition could meanwhile protect ovarian function in mice with chemical carcinogen-induced in-situ ovarian cancers or with ovarian cancer cell transplantation. This study suggested that BIN2 inhibition could both suppress ovarian tumorigenesis and protect ovarian fertility, but through distinct mechanisms. Overall design: To investigate the function Bin2 inhibition in the suppression of ovarian cancer progression, we treated A2780 cell with BPP peptide which competed the phosphorylation site of BIN2 .  We then performed gene expression profiling analysis using data Obtained from RNA seq of A2780 treated with BPP and TAT peptide.