A novel protein encoded by circINSIG1 reprograms cholesterol metabolism by promoting the ubiquitin-dependent degradation of INSIG1 in colorectal cancer.

BACKGROUND: Hypoxia is a hallmark of solid tumors and leads to the metabolic reprogramming of cancer cells. The role of epigenetic regulation between hypoxia and aberrant cholesterol metabolism in colorectal cancer (CRC) remains elusive. METHODS: Hypoxia-responsive circular RNAs (circRNAs) were identified by high throughput RNA sequencing between CRC cells cultured under normoxia or hypoxia. The protein-coding potential of circINSIG1 was identified by polysome profiling and LC-MS. The function of circINSIG1 was validated in vitro and in vivo by gain or loss of function assays. Mechanistic results were concluded by immunoprecipitation analyses. RESULTS: A novel hypoxia-responsive circRNA named circINSIG1 was identified, which was upregulated in CRC tissues and correlated with advanced clinical stages and poor survival. Mechanistically, circINSIG1 encoded a 121 amino acid protein circINSIG1-121 to promote K48-linked ubiquitination of the critical cholesterol metabolism regulator INSIG1 at lysine 156 and 158 by recruiting CUL5-ASB6 complex, a ubiquitin E3 ligase complex, thereby inducing cholesterol biosynthesis to promote CRC proliferation and metastasis. The orthotopic xenograft tumor models and patient-derived xenograft models further identified the role of circINSIG1 in CRC progression and potential therapeutic target of CRC. CONCLUSIONS: circINSIG1 presents an epigenetic mechanism which provides insights into the crosstalk between hypoxia and cholesterol metabolism, and provides a promising therapeutic target for the treatment of CRC.

Transanal total mesorectal excision combined with intersphincteric resection has similar long-term oncological outcomes to laparoscopic abdominoperineal resection in low rectal cancer: a propensity score-matched cohort study.

Background: Transanal total mesorectal excision (taTME) or intersphincteric resection (ISR) has recently proven to be a valid and safe surgical procedure for low rectal cancer. However, studies focusing on the combination of these two technologies are limited. This study aimed to evaluate perioperative results, long-term oncologic outcomes, and anorectal functions of patients with low rectal cancer undergoing taTME combined with ISR, by comparing with those of patients undergoing laparoscopic abdominoperineal resection (laAPR). Methods: After 1:1 propensity score matching, 200 patients with low rectal cancer who underwent laAPR (n = 100) or taTME combined with ISR (n = 100) between September 2013 and November 2019 were included. Patient demographics, clinicopathological characteristics, oncological outcomes, and anal functional results were analysed. Results: Patients in the taTME-combined-with-ISR group had less intraoperative blood loss (79.6 ± 72.6 vs 107.3 ± 65.1 mL, P = 0.005) and a lower rate of post-operative complications (22.0% vs 44.0%, P < 0.001) than those in the laAPR group. The overall local recurrence rates were 7.0% in both groups within 3 years after surgery. The 3-year disease-free survival rates were 86.3% in the taTME-combined-with-ISR group and 75.1% in the laAPR group (P = 0.056), while the 3-year overall survival rates were 96.7% and 94.2%, respectively (P = 0.319). There were 39 patients (45.3%) in the taTME-combined-with-ISR group who developed major low anterior resection syndrome, whereas 61 patients (70.9%) had good post-operative anal function (Wexner incontinence score ≤ 10). Conclusion: We found similar long-term oncological outcomes for patients with low rectal cancer undergoing laAPR and those undergoing taTME combined with ISR. Patients receiving taTME combined with ISR had acceptable post-operative anorectal function.