Investigating the role of HOTTIP, HOXA13 and PSIP1 in cancer.

Worldwide, colorectal cancer (CRC) is the third most prevalent cancer and prostate cancer (PCa) is the second most prominent cancer in men. Treatments for both CRC and PCa have greatly improved over the last 10-20 years; however, there is still a high mortality rate for both cancers. There is therefore a great need to better understand the factors that drive disease development and progression, and therapy resistance. Long non-coding RNAs (lncRNAs) have gained attention in recent years as potential therapeutic targets for cancer. HOTTIP is one such lncRNA that has previously been implicated in CRC and PCa. HOTTIP is located on the 5’ end of the HOXA locus and regulates nearby HOXA genes including HOXA13 in cis. It has previously been shown that HOTTIP and HOXA genes are regulated by the oncogenic PSIP1 protein. Using both siRNA mediated knockdown and CRISPR-Cas9 mediated genetic knockout approaches, the role of HOTTIP, HOXA13 and PSIP1 were investigated in both CRC and PCa. Through loss of function studies, depletion of HOTTIP, HOXA13 and PSIP1 led to increased sensitivity to chemotherapeutic drugs. This has not previously been observed for HOXA13 in PCa, or HOTTIP, HOXA13 and PSIP1 in CRC. These observations suggest that further study of these genes may help with understanding therapy resistance in CRC and PCa. More in-depth characterisation of how these genes are regulated may identify methods to enhance therapy response or re-sensitise tumours to chemotherapy.